bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2021–12–19
forty papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Identification of Potential circRNA-microRNA-mRNA Regulatory Network in Skeletal Muscle.
  2. KLF15 overexpression in myocytes fails to ameliorate ALS-related pathology or extend the lifespan of SOD1G93A mice.
  3. Aging Does Not Exacerbate Muscle Loss During Denervation and Lends Unique Muscle-Specific Atrophy Resistance With Akt Activation.
  4. Loss of Nup210 results in muscle repair delays and age-associated alterations in muscle integrity.
  5. TGM2 positively regulates myoblast differentiation via enhancing the mTOR signaling.
  6. Exosomes derived from inflammatory myoblasts promote M1 polarization and break the balance of myoblast proliferation/differentiation.
  7. ViaFuse: Fiji macros to calculate skeletal muscle cell viability and fusion index.
  8. Genome-wide identification of enhancers and transcription factors regulating the myogenic differentiation of bovine satellite cells.
  9. Genetic correction strategies for Duchenne Muscular Dystrophy and their impact on the heart.
  10. Innovation in culture systems to study muscle complexity.
  11. Low-Grade Systemic Inflammation Interferes with Anabolic and Catabolic Characteristics of the Aged Human Skeletal Muscle.
  12. Deletion of SA β-Gal+ cells using senolytics improves muscle regeneration in old mice.
  13. RANKL Blockade Reduces Cachexia and Bone Loss Induced by Non-Metastatic Ovarian Cancer in Mice.
  14. Acute exposure to extracellular BTP2 does not inhibit Ca2+ release during EC coupling in intact skeletal muscle fibers.
  15. Walking Exercise Therapy Effects on Lower Extremity Skeletal Muscle in Peripheral Artery Disease.
  16. MicroRNA-193b impairs muscle growth in mouse models of type 2 diabetes by targeting the PDK1/Akt signalling pathway.
  17. Transcriptomic adaptation during skeletal muscle habituation to eccentric or concentric exercise training.
  18. MicroRNA is a potential target for therapies to improve the physiological function of skeletal muscle after trauma.
  19. SENP2 is vital for optimal insulin signaling and insulin-stimulated glycogen synthesis in human skeletal muscle cells.
  20. ALY688 elicits adiponectin-mimetic signaling and improves insulin action in skeletal muscle cells.
  21. Chronic treatment with terbutaline increases glucose and oleic acid oxidation and protein synthesis in cultured human myotubes.
  22. Extracellular vesicle secretion is tissue-dependent ex vivo and skeletal muscle myofiber extracellular vesicles reach the circulation in vivo.
  23. Multiple regions of junctin drive interaction with calsequestrin-1 and localization at triads in skeletal muscle.
  24. Potential Benefits of a Minimal Dose Eccentric Resistance Training Paradigm to Combat Sarcopenia and Age-Related Muscle and Physical Function Deficits in Older Adults.
  25. Human and mouse muscle transcriptomic analyses identify insulin receptor mRNA downregulation in hyperinsulinemia-associated insulin resistance.
  26. The small molecule SERCA activator CDN1163 increases energy metabolism in human skeletal muscle cells.
  27. CHOP is Dispensable for Exercise-Induced Increases in GDF15.
  28. Resistance Training as Treatment for Sarcopenia: Examining Sex-Related Differences in Physiology and Response.
  29. Effects of an acute exercise bout in hypoxia on extracellular vesicle release in healthy and prediabetic subjects.
  30. Poly C Binding Protein 2 dependent nuclear retention of the utrophin-A mRNA in C2C12 cells.
  31. Hallmarks of exercised heart.
  32. Do skeletal muscle composition and gene expression as well as acute exercise-induced serum adaptations in older adults depend on fitness status?
  33. The Severity of Muscle Performance Deterioration in Sarcopenia Correlates With Circulating Muscle Tissue-Specific miRNAs.
  34. Differential Autophagy Response in Men and Women After Muscle Damage.
  35. Paracrine FGFs target skeletal muscle to exert potent anti-hyperglycemic effects.
  36. Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance.
  37. The Abl-interactor Abi suppresses the function of the BRAG2 GEF family member Schizo.
  38. Characterization of patients with Becker muscular dystrophy by histology, magnetic resonance imaging, function, and strength assessments.
  39. Effects of different exercise training modes on muscle strength and physical performance in older people with sarcopenia: a systematic review and meta-analysis.
  40. Nutrition challenges of cancer cachexia.
  1. Front Mol Biosci. 2021 ;8 762185
    Identification of Potential circRNA-microRNA-mRNA Regulatory Network in Skeletal Muscle.
    Arundhati Das, Sharmishtha Shyamal, Tanvi Sinha, Smruti Sambhav Mishra, Amaresh C Panda.
      Circular RNAs (circRNAs) are a newly discovered family of regulatory RNAs generated through backsplicing. Genome-wide profiling of circRNAs found that circRNAs are ubiquitously expressed and regulate gene expression by acting as a sponge for RNA-binding proteins (RBPs) and microRNAs (miRNAs). To identify circRNAs expressed in mouse skeletal muscle, we performed high-throughput RNA-sequencing of circRNA-enriched gastrocnemius muscle RNA samples, which identified more than 1,200 circRNAs. In addition, we have identified more than 14,000 and 15,000 circRNAs in aging human skeletal muscle tissue and satellite cells, respectively. A subset of abundant circRNAs was analyzed by RT-PCR, Sanger sequencing, and RNase R digestion assays to validate their expression in mouse skeletal muscle tissues. Analysis of the circRNA-miRNA-mRNA regulatory network revealed that conserved circNfix might associate with miR-204-5p, a suppressor of myocyte enhancer factor 2c (Mef2c) expression. To support the hypothesis that circNfix might regulate myogenesis by controlling Mef2c expression, silencing circNfix moderately reduced Mef2c mRNA expression and inhibited C2C12 differentiation. We propose that circNfix promotes MEF2C expression during muscle cell differentiation in part by acting as a sponge for miR-204-5p.
    Keywords:  ceRNA; circular RNA; microRNA; myogenesis; skeletal muscle
    DOI:  https://doi.org/10.3389/fmolb.2021.762185
  2. Neurobiol Dis. 2021 Dec 11. pii: S0969-9961(21)00332-6. [Epub ahead of print]162 105583
    KLF15 overexpression in myocytes fails to ameliorate ALS-related pathology or extend the lifespan of SOD1G93A mice.
    Ryan Massopust, Devin Juros, Dillon Shapiro, Mikayla Lopes, Saptarsi M Haldar, Thomas Taetzsch, Gregorio Valdez.
      Amyotrophic Lateral Sclerosis (ALS) is a currently incurable disease that causes progressive motor neuron loss, paralysis and death. Skeletal muscle pathology occurs early during the course of ALS. It is characterized by impaired mitochondrial biogenesis, metabolic dysfunction and deterioration of the neuromuscular junction (NMJ), the synapse through which motor neurons communicate with muscles. Therefore, a better understanding of the molecules that underlie this pathology may lead to therapies that slow motor neuron loss and delay ALS progression. Kruppel Like Factor 15 (KLF15) has been identified as a transcription factor that activates alternative metabolic pathways and NMJ maintenance factors, including Fibroblast Growth Factor Binding Protein 1 (FGFBP1), in skeletal myocytes. In this capacity, KLF15 has been shown to play a protective role in Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), however its role in ALS has not been evaluated. Here, we examined whether muscle-specific KLF15 overexpression promotes the health of skeletal muscles and NMJs in the SOD1G93A ALS mouse model. We show that muscle-specific KLF15 overexpression did not elicit a significant beneficial effect on skeletal muscle atrophy, NMJ health, motor function, or survival in SOD1G93A ALS mice. Our findings suggest that, unlike in mouse models of DMD and SMA, KLF15 overexpression has a minimal impact on ALS disease progression in SOD1G93A mice.
    Keywords:  ALS; FGFBP1; KLF15; NMJ
    DOI:  https://doi.org/10.1016/j.nbd.2021.105583
  3. Front Physiol. 2021 ;12 779547
    Aging Does Not Exacerbate Muscle Loss During Denervation and Lends Unique Muscle-Specific Atrophy Resistance With Akt Activation.
    Jae-Sung You, Jie Chen.
      Sarcopenia, or age-related skeletal muscle atrophy and weakness, imposes significant clinical and economic burdens on affected patients and societies. Neurological degeneration, such as motoneuron death, has been recognized as a key contributor to sarcopenia. However, little is known about how aged/sarcopenic muscle adapts to this denervation stress. Here, we show that mice at 27months of age exhibit clear signs of sarcopenia but no accelerated denervation-induced muscle atrophy when compared to 8-month-old mice. Surprisingly, aging lends unique atrophy resistance to tibialis anteria muscle, accompanied by an increase in the cascade of mammalian target of rapamycin complex 1 (mTORC1)-independent anabolic events involving Akt signaling, rRNA biogenesis, and protein synthesis during denervation. These results expand our understanding of age-dependent stress responses and may help develop better countermeasures to sarcopenia.
    Keywords:  Akt; aging; denervation; mTORC1; muscle; protein synthesis; rRNA
    DOI:  https://doi.org/10.3389/fphys.2021.779547
  4. Life Sci Alliance. 2022 Mar;pii: e202101216. [Epub ahead of print]5(3):
    Loss of Nup210 results in muscle repair delays and age-associated alterations in muscle integrity.
    Stephen Sakuma, Ethan Ys Zhu, Marcela Raices, Pan Zhang, Rabi Murad, Maximiliano A D'Angelo.
      Nuclear pore complexes, the channels connecting the nucleus with the cytoplasm, are built by multiple copies of ∼30 proteins called nucleoporins. Recent evidence has exposed that nucleoporins can play cell type-specific functions. Despite novel discoveries into the cellular functions of nucleoporins, their role in the regulation of mammalian tissue physiology remains mostly unexplored because of a limited number of nucleoporin mouse models. Here we show that ablation of Nup210/Gp210, a nucleoporin previously identified to play a role in myoblast differentiation and Zebrafish muscle maturation, is dispensable for skeletal muscle formation and growth in mice. We found that although primary satellite cells from Nup210 knockout mice can differentiate, these animals show delayed muscle repair after injury. Moreover, Nup210 knockout mice display an increased percentage of centrally nucleated fibers and abnormal fiber type distribution as they age. Muscle function experiments also exposed that Nup210 is required for muscle endurance during voluntary running. Our findings indicate that in mammals, Nup210 is important for the maintenance of skeletal muscle integrity and for proper muscle function providing novel insights into the in vivo roles of nuclear pore complex components.
    DOI:  https://doi.org/10.26508/lsa.202101216
  5. Biochim Biophys Acta Mol Cell Res. 2021 Dec 11. pii: S0167-4889(21)00227-5. [Epub ahead of print]1869(3): 119173
    TGM2 positively regulates myoblast differentiation via enhancing the mTOR signaling.
    Dongdong Wang, Dandan Zhao, Yuan Li, Tingjun Dai, Fuchen Liu, Chuanzhu Yan.
      Myoblast differentiation is an essential process for the control of muscle regeneration. However, the intrinsic mechanisms underlying this dynamic process are still not well clarified. Herein, we identified transglutaminase type 2 (TGM2) as a novel regulator of muscle differentiation and regeneration in vitro and in vivo. Specifically, knockdown of TGM2 suppresses whereas overexpression of TGM2 promotes myoblast differentiation in differentiating C2C12 cells. Mechanistic studies revealed that TGM2 promotes C2C12 myoblast differentiation via enhancing GPR56 mediated activation of the mTOR signaling. Additionally, lentivirus mediated knockdown of TGM2 hinders the regeneration of muscles in a BaCl2 induced skeletal muscle injury model of mice. Finally, we found that both TGM2 and activation of the mTOR signaling are up-regulated in muscles of patients with immune-mediated necrotizing myopathy (IMNM), especially in the regenerating myofibers. Collectively, our research demonstrates that TGM2 positively regulates muscle differentiation and regeneration through facilitating the myogenic mTOR signaling, which might be a potential target of therapy for skeletal muscle injury.
    Keywords:  C2C12; GPR56; Muscle regeneration; Myoblast differentiation; TGM2; mTOR
    DOI:  https://doi.org/10.1016/j.bbamcr.2021.119173
  6. World J Stem Cells. 2021 Nov 26. 13(11): 1762-1782
    Exosomes derived from inflammatory myoblasts promote M1 polarization and break the balance of myoblast proliferation/differentiation.
    Zhi-Wen Luo, Ya-Ying Sun, Jin-Rong Lin, Bei-Jie Qi, Ji-Wu Chen.
       BACKGROUND: Acute muscle injuries are one of the most common injuries in sports. Severely injured muscles are prone to re-injury due to fibrotic scar formation caused by prolonged inflammation. How to regulate inflammation and suppress fibrosis is the focus of promoting muscle healing. Recent studies have found that myoblasts and macrophages play important roles in the inflammatory phase following muscle injury; however, the crosstalk between these two types of cells in the inflammatory environment, particularly the exosome-related mechanisms, had not been well studied.
    AIM: To evaluate the effects of exosomes from inflammatory C2C12 myoblasts (IF-C2C12-Exos) on macrophage polarization and myoblast proliferation/differentiation.
    METHODS: A model of inflammation was established in vitro by lipopolysaccharide stimulation of myoblasts. C2C12-Exos were isolated and purified from the supernatant of myoblasts by gradient centrifugation. Multiple methods were used to identify the exosomes. Gradient concentrations of IF-C2C12-Exos were added to normal macrophages and myoblasts. PKH67 fluorescence tracing was used to identify the interaction between exosomes and cells. Microscopic morphology, Giemsa stain, and immunofluorescence were carried out for histological analysis. Additionally, ELISA assays, flow cytometry, and western blot were conducted to analyze molecular changes. Moreover, myogenic proliferation was assessed by the BrdU test, scratch assay, and CCK-8 assay.
    RESULTS: We found that the PKH-67-marked C2C12-Exos can be endocytosed by both macrophages and myoblasts. IF-C2C12-Exos induced M1 macrophage polarization and suppressed the M2 phenotype in vitro. In addition, these exosomes also stimulated the inflammatory reactions of macrophages. Furthermore, we demonstrated that IF-C2C12-Exos disrupted the balance of myoblast proliferation/differentiation, leading to enhanced proliferation and suppressed fibrogenic/myogenic differentiation.
    CONCLUSION: IF-C2C12-Exos can induce M1 polarization, resulting in a sustained and aggravated inflammatory environment that impairs myoblast differentiation, and leads to enhanced myogenic proliferation. These results demonstrate why prolonged inflammation occurs after acute muscle injury and provide a new target for the regulation of muscle regeneration.
    Keywords:  C2C12 myoblast; Differentiation; Exosomes; Inflammation; Macrophage polarization; Proliferation
    DOI:  https://doi.org/10.4252/wjsc.v13.i11.1762
  7. Skelet Muscle. 2021 Dec 16. 11(1): 28
    ViaFuse: Fiji macros to calculate skeletal muscle cell viability and fusion index.
    Emma Rose Hinkle, Tasneem Omar Essader, Gabrielle Marie Gentile, Jimena Giudice.
       BACKGROUND: Measuring biological features of skeletal muscle cells is difficult because of their unique morphology and multinucleate nature upon differentiation. Here, we developed a new Fiji macro package called ViaFuse (that stands for viability and fusion) to measure skeletal muscle cell viability and differentiation. To test ViaFuse, we utilized immunofluorescence images of differentiated myotubes where the capping actin protein of muscle z-line subunit beta (CAPZB) was depleted in comparison with control cells.
    RESULTS: We compared the values achieved using the ViaFuse macros first with manual quantification performed by researchers and second with those obtained utilizing the MATLAB muscle-centric software MyoCount. We observed a high degree of correlation between all methods of quantification.
    CONCLUSIONS: ViaFuse can detect the borders of myotubes and identify nuclear clumps which have been limitations of previous muscle-centric imaging software. The ViaFuse macros require little computer power or space to run and user inputs to the ViaFuse macros are minimal, thereby automating the analysis process in a quick, easy, and accurate fashion. Additionally, the ViaFuse macros work with Fiji, an existing imaging software widely used by skeletal muscle researchers. Furthermore, ViaFuse is compatible with many computer systems, has a very intuitive interface, and does not require prior complex mathematical knowledge. Therefore, we propose ViaFuse as a robust and meticulous method to quantify skeletal muscle cell viability and differentiation.
    Keywords:  C2C12 cell differentiation quantification; Fusion index; Myogenesis; Skeletal muscle; Skeletal muscle cell software
    DOI:  https://doi.org/10.1186/s13395-021-00284-3
  8. BMC Genomics. 2021 Dec 16. 22(1): 901
    Genome-wide identification of enhancers and transcription factors regulating the myogenic differentiation of bovine satellite cells.
    Pengcheng Lyu, Robert E Settlage, Honglin Jiang.
       BACKGROUND: Satellite cells are the myogenic precursor cells in adult skeletal muscle. The objective of this study was to identify enhancers and transcription factors that regulate gene expression during the differentiation of bovine satellite cells into myotubes.
    RESULTS: Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) was performed to identify genomic regions where lysine 27 of H3 histone is acetylated (H3K27ac), i.e., active enhancers, from bovine satellite cells before and during differentiation into myotubes. A total of 19,027 and 47,669 H3K27ac-marked enhancers were consistently identified from two biological replicates of before- and during-differentiation bovine satellite cells, respectively. Of these enhancers, 5882 were specific to before-differentiation, 35,723 to during-differentiation, and 13,199 common to before- and during-differentiation bovine satellite cells. Whereas most of the before- or during-differentiation-specific H3K27ac-marked enhancers were located distally to the transcription start site, the enhancers common to before- and during-differentiation were located both distally and proximally to the transcription start site. The three sets of H3K27ac-marked enhancers were associated with functionally different genes and enriched with different transcription factor binding sites. Specifically, many of the H3K27ac-marked enhancers specific to during-differentiation bovine satellite cells were associated with genes involved in muscle structure and development, and were enriched with binding sites for the MyoD, AP-1, KLF, TEAD, and MEF2 families of transcription factors. A positive role was validated for Fos and FosB, two AP-1 family transcription factors, in the differentiation of bovine satellite cells into myotubes by siRNA-mediated knockdown.
    CONCLUSIONS: Tens of thousands of H3K27ac-marked active enhancers have been identified from bovine satellite cells before or during differentiation. These enhancers contain binding sites not only for transcription factors whose role in satellite cell differentiation is well known but also for transcription factors whose role in satellite cell differentiation is unknown. These enhancers and transcription factors are valuable resources for understanding the complex mechanism that mediates gene expression during satellite cell differentiation. Because satellite cell differentiation is a key step in skeletal muscle growth, the enhancers, the transcription factors, and their target genes identified in this study are also valuable resources for identifying and interpreting skeletal muscle trait-associated DNA variants in cattle.
    Keywords:  Cattle; Enhancer; Skeletal muscle; Transcription factor
    DOI:  https://doi.org/10.1186/s12864-021-08224-7
  9. Prog Pediatr Cardiol. 2021 Dec;pii: 101460. [Epub ahead of print]63
    Genetic correction strategies for Duchenne Muscular Dystrophy and their impact on the heart.
    Jamie R Johnston, Elizabeth M McNally.
       Background: Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder with early childhood onset characterized by profound loss of muscle strength and associated cardiomyopathy. DMD affects is most often caused by deletions involving single or multiple exons that disrupt the open reading frame of the DMD gene. Mutations causing loss or premature truncation of dystrophin result in dystrophin protein deficiency, which renders the plasma membrane of skeletal myofibers and cardiomyocytes weakened.
    Aim of Review: Genetic correction is in use to treat DMD, since several drugs have been already approved which partially restore dystrophin production through the use of antisense oligonucleotides. There are multiple ongoing clinical trials to evaluate the efficacy of treating DMD with micro-dystrophins delivered by adeno-associated viruses. Future approaches entail gene editing to target the single copy of the DMD gene on the X-chromosome. The primary, near-term goal is restoration of skeletal muscle dystrophin, and for some of these treatments, the efficacy in the heart is not fully known. Here, we discuss the anticipated cardiac outcomes of dystrophin-targeted therapies, and how this information informs genomic medicine for cardiomyopathies, especially in childhood.
    Key Scientific Concepts of Review: Many genetic treatment strategies are being implemented to treat DMD. Since most preclinical testing has focused on skeletal muscle, there is a gap in knowledge about the expected effects of these approaches on cardiac genetic correction and cardiomyopathy progression in DMD. Additional study is needed.
    Keywords:  Duchenne muscular dystrophy; dilated cardiomyopathy; gene therapy; genome editing; heart failure; pediatrics
    DOI:  https://doi.org/10.1016/j.ppedcard.2021.101460
  10. Exp Cell Res. 2021 Dec 11. pii: S0014-4827(21)00522-X. [Epub ahead of print] 112966
    Innovation in culture systems to study muscle complexity.
    Louise A Moyle, Sadegh Davoudi, Penney M Gilbert.
      Endogenous skeletal muscle development, regeneration, and pathology are extremely complex processes, influenced by local and systemic factors. Unpinning how these mechanisms function is crucial for fundamental biology and to develop therapeutic interventions for genetic disorders, but also conditions like sarcopenia and volumetric muscle loss. Ex vivo skeletal models range from two- and three-dimensional primary cultures of satellite stem cell-derived myoblasts grown alone or in co-culture, to single muscle myofibers, myobundles, and whole tissues. Together, these systems provide the opportunity to gain mechanistic insights of stem cell behavior, cell-cell interactions, and mature muscle function in simplified systems, without confounding variables. Here, we highlight recent advances (published in the last 5 years) using in vitro primary cells and ex vivo skeletal muscle models, and summarize the new insights, tools, datasets, and screening methods they have provided. Finally, we highlight the opportunity for exponential advance of skeletal muscle knowledge, with spatiotemporal resolution, that is offered by guiding the study of muscle biology and physiology with in silico modelling and implementing high-content cell biology systems and ex vivo physiology platforms.
    Keywords:  Explants; In vitro; Myofiber; Physiology; Satellite cell; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.yexcr.2021.112966
  11. Oxid Med Cell Longev. 2021 ;2021 8376915
    Low-Grade Systemic Inflammation Interferes with Anabolic and Catabolic Characteristics of the Aged Human Skeletal Muscle.
    Dimitrios Draganidis, Athanasios Z Jamurtas, Niki Chondrogianni, George Mastorakos, Tobias Jung, Tilman Grune, Constantinos Papadopoulos, Konstantinos Papanikolaou, Ioannis Papassotiriou, Nikoletta Papaevgeniou, Athanasios Poulios, Alexios Batrakoulis, Chariklia K Deli, Kalliopi Georgakouli, Athanasios Chatzinikolaou, Leonidas G Karagounis, Ioannis G Fatouros.
      Aging is associated with the development of chronic low-grade systemic inflammation (LGSI) characterized by increased circulating levels of proinflammatory cytokines and acute phase proteins such as C-reactive protein (CRP). Collective evidence suggests that elevated levels of inflammatory mediators such as CRP, interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α) are correlated with deteriorated skeletal muscle mass and function, though the molecular footprint of this observation in the aged human skeletal muscle remains obscure. Based on animal models showing impaired protein synthesis and enhanced degradation in response to LGSI, we compared here the response of proteolysis- and protein synthesis-related signaling proteins as well as the satellite cell and amino acid transporter protein content between healthy older adults with increased versus physiological blood hs-CRP levels in the fasted (basal) state and after an anabolic stimulus comprised of acute resistance exercise (RE) and protein feeding. Our main findings indicate that older adults with increased hs-CRP levels demonstrate (i) increased proteasome activity, accompanied by increased protein carbonylation and IKKα/β phosphorylation; (ii) reduced Pax7+ satellite cells; (iii) increased insulin resistance, at the basal state; and (iv) impaired S6 ribosomal protein phosphorylation accompanied by hyperinsulinemia following an acute RE bout combined with protein ingestion. Collectively, these data provide support to the concept that age-related chronic LGSI may upregulate proteasome activity via induction of the NF-κB signaling and protein oxidation and impair the insulin-dependent anabolic potential of human skeletal muscle.
    DOI:  https://doi.org/10.1155/2021/8376915
  12. Aging Cell. 2021 Dec 13. e13528
    Deletion of SA β-Gal+ cells using senolytics improves muscle regeneration in old mice.
    Cory M Dungan, Kevin A Murach, Christopher J Zdunek, Zuo Jian Tang, Georgia L VonLehmden, Camille R Brightwell, Zachary Hettinger, Davis A Englund, Zheng Liu, Christopher S Fry, Antonio Filareto, Michael Franti, Charlotte A Peterson.
      Systemic deletion of senescent cells leads to robust improvements in cognitive, cardiovascular, and whole-body metabolism, but their role in tissue reparative processes is incompletely understood. We hypothesized that senolytic drugs would enhance regeneration in aged skeletal muscle. Young (3 months) and old (20 months) male C57Bl/6J mice were administered the senolytics dasatinib (5 mg/kg) and quercetin (50 mg/kg) or vehicle bi-weekly for 4 months. Tibialis anterior (TA) was then injected with 1.2% BaCl2 or PBS 7- or 28 days prior to euthanization. Senescence-associated β-Galactosidase positive (SA β-Gal+) cell abundance was low in muscle from both young and old mice and increased similarly 7 days following injury in both age groups, with no effect of D+Q. Most SA β-Gal+ cells were also CD11b+ in young and old mice 7- and 14 days following injury, suggesting they are infiltrating immune cells. By 14 days, SA β-Gal+/CD11b+ cells from old mice expressed senescence genes, whereas those from young mice expressed higher levels of genes characteristic of anti-inflammatory macrophages. SA β-Gal+ cells remained elevated in old compared to young mice 28 days following injury, which were reduced by D+Q only in the old mice. In D+Q-treated old mice, muscle regenerated following injury to a greater extent compared to vehicle-treated old mice, having larger fiber cross-sectional area after 28 days. Conversely, D+Q blunted regeneration in young mice. In vitro experiments suggested D+Q directly improve myogenic progenitor cell proliferation. Enhanced physical function and improved muscle regeneration demonstrate that senolytics have beneficial effects only in old mice.
    Keywords:  regeneration; satellite cells; senescence; senolytics; skeletal muscle
    DOI:  https://doi.org/10.1111/acel.13528
  13. J Bone Miner Res. 2021 Dec 13.
    RANKL Blockade Reduces Cachexia and Bone Loss Induced by Non-Metastatic Ovarian Cancer in Mice.
    Fabrizio Pin, Alexander J Jones, Joshua R Huot, Ashok Narasimhan, Teresa A Zimmers, Lynda F Bonewald, Andrea Bonetto.
      Tumor- and bone-derived soluble factors have been proposed to participate in the alterations of skeletal muscle size and function in cachexia. We previously showed that mice bearing ovarian cancer (OvCa) exhibit cachexia associated with marked bone loss, whereas bone-targeting agents, such as bisphosphonates, are able to preserve muscle mass in animals exposed to anticancer drugs. De-identified CT images and plasma samples from female patients affected with OvCa were used for body composition assessment and quantification of circulating cross-linked C-telopeptide type I (CTX-I) and receptor activator of NF-kB ligand (RANKL), respectively. Female mice bearing ES-2 tumors were used to characterize cancer- and RANKL-associated effects on muscle and bone. Murine C2C12 and human HSMM myotube cultures were used to determine the OvCa- and RANKL-dependent effects on myofiber size. To the extent of isolating new regulators of bone and muscle in cachexia, here we demonstrate that subjects affected with OvCa display evidence of cachexia and increased bone turnover. Similarly, mice carrying OvCa present high RANKL levels. By using in vitro and in vivo experimental models, we found that elevated circulating RANKL is sufficient to cause skeletal muscle atrophy and bone resorption, whereas bone preservation by means of antiresorptive and anti-RANKL treatments concurrently benefit muscle mass and function in cancer cachexia. Altogether, our data contribute to identifying RANKL as a novel therapeutic target for the treatment of musculoskeletal complications associated with RANKL-expressing non-metastatic cancers. © 2021 American Society for Bone and Mineral Research (ASBMR).
    Keywords:  ANTIRESORPTIVE TREATMENTS; BONE; CACHEXIA; CANCER; MUSCLE; RANKL
    DOI:  https://doi.org/10.1002/jbmr.4480
  14. J Gen Physiol. 2022 Sep 05. pii: e202112976. [Epub ahead of print]154(9):
    Acute exposure to extracellular BTP2 does not inhibit Ca2+ release during EC coupling in intact skeletal muscle fibers.
    Lan Wei-LaPierre, Linda Groom, Robert T Dirksen.
      The inhibitor of store-operated Ca2+ entry (SOCE) BTP2 was reported to inhibit ryanodine receptor Ca2+ leak and electrically evoked Ca2+ release from the sarcoplasmic reticulum when introduced into mechanically skinned muscle fibers. However, it is unclear how effects of intracellular application of a highly lipophilic drug like BTP2 on Ca2+ release during excitation-contraction (EC) coupling compare with extracellular exposure in intact muscle fibers. Here, we address this question by quantifying the effect of short- and long-term exposure to 10 and 20 µM BTP2 on the magnitude and kinetics of electrically evoked Ca2+ release in intact mouse flexor digitorum brevis muscle fibers. Our results demonstrate that neither the magnitude nor the kinetics of electrically evoked Ca2+ release evoked during repetitive electrical stimulation were altered by brief exposure (2 min) to either BTP2 concentration. However, BTP2 did reduce the magnitude of electrically evoked Ca2+ release in intact fibers when applied extracellularly for a prolonged period of time (30 min at 10 µM or 10 min at 20 µM), consistent with slow diffusion of the lipophilic drug across the plasma membrane. Together, these results indicate that the time course and impact of BTP2 on Ca2+ release during EC coupling in skeletal muscle depends strongly on whether the drug is applied intracellularly or extracellularly. Further, these results demonstrate that electrically evoked Ca2+ release in intact muscle fibers is unaltered by extracellular application of 10 µM BTP2 for <25 min, validating this use to assess the role of SOCE in the absence of an effect on EC coupling.
    DOI:  https://doi.org/10.1085/jgp.202112976
  15. Circ Res. 2021 Jun 11. 128(12): 1851-1867
    Walking Exercise Therapy Effects on Lower Extremity Skeletal Muscle in Peripheral Artery Disease.
    Mary M McDermott, Sudarshan Dayanidhi, Kate Kosmac, Sunil Saini, Joshua Slysz, Christiaan Leeuwenburgh, Lisa Hartnell, Robert Sufit, Luigi Ferrucci.
      Walking exercise is the most effective noninvasive therapy that improves walking ability in peripheral artery disease (PAD). Biologic mechanisms by which exercise improves walking in PAD are unclear. This review summarizes evidence regarding effects of walking exercise on lower extremity skeletal muscle in PAD. In older people without PAD, aerobic exercise improves mitochondrial activity, muscle mass, capillary density, and insulin sensitivity in skeletal muscle. However, walking exercise increases lower extremity ischemia in people with PAD, and therefore, mechanisms by which this exercise improves walking may differ between people with and without PAD. Compared with people without PAD, gastrocnemius muscle in people with PAD has greater mitochondrial impairment, increased reactive oxygen species, and increased fibrosis. In multiple small trials, walking exercise therapy did not consistently improve mitochondrial activity in people with PAD. In one 12-week randomized trial of people with PAD randomized to supervised exercise or control, supervised treadmill exercise increased treadmill walking time from 9.3 to 15.1 minutes, but simultaneously increased the proportion of angular muscle fibers, consistent with muscle denervation (from 7.6% to 15.6%), while angular myofibers did not change in the control group (from 9.1% to 9.1%). These findings suggest an adaptive response to exercise in PAD that includes denervation and reinnervation, an adaptive process observed in skeletal muscle of people without PAD during aging. Small studies have not shown significant effects of exercise on increased capillary density in lower extremity skeletal muscle of participants with PAD, and there are no data showing that exercise improves microcirculatory delivery of oxygen and nutrients in patients with PAD. However, the effects of supervised exercise on increased plasma nitrite abundance after a treadmill walking test in people with PAD may be associated with improved lower extremity skeletal muscle perfusion and may contribute to improved walking performance in response to exercise in people with PAD. Randomized trials with serial, comprehensive measures of muscle biology, and physiology are needed to clarify mechanisms by which walking exercise interventions improve mobility in PAD.
    Keywords:  exercise; ischemia; mitochondria; perfusion; peripheral artery disease; plasma; skeletal muscle
    DOI:  https://doi.org/10.1161/CIRCRESAHA.121.318242
  16. Diabetologia. 2021 Dec 16.
    MicroRNA-193b impairs muscle growth in mouse models of type 2 diabetes by targeting the PDK1/Akt signalling pathway.
    Shu Yang, Guangyan Yang, Han Wu, Lin Kang, Jiaqing Xiang, Peilin Zheng, Shanhu Qiu, Zhen Liang, Yan Lu, Lijing Jia.
       AIMS/HYPOTHESIS: Type 2 diabetes is associated with a reduction in skeletal muscle mass; however, how the progression of sarcopenia is induced and regulated remains largely unknown. We aimed to find out whether a specific microRNA (miR) may contribute to skeletal muscle atrophy in type 2 diabetes.
    METHODS: Adeno-associated virus (AAV)-mediated skeletal muscle miR-193b overexpression in C57BLKS/J mice, and skeletal muscle miR-193b deficiency in db/db mice were used to explore the function of miR-193b in muscle loss. In C57BL/6 J mice, tibialis anterior-specific deletion of 3-phosphoinositide-dependent protein kinase-1 (PDK1), mediated by in situ AAV injection, was used to confirm whether miR-193b regulates muscle growth through PDK1. Serum miR-193b levels were also analysed in healthy individuals (n = 20) and those with type 2 diabetes (n = 20), and correlations of miR-193b levels with HbA1c, fasting blood glucose (FBG), body composition, triacylglycerols and C-peptide were assessed.
    RESULTS: In this study, we found that serum miR-193b levels increased in individuals with type 2 diabetes and negatively correlated with muscle mass in these participants. Functional studies further showed that AAV-mediated overexpression of miR-193b induced muscle loss and dysfunction in healthy mice. In contrast, suppression of miR-193b attenuated muscle loss and dysfunction in db/db mice. Mechanistic analysis revealed that miR-193b could target Pdk1 expression to inactivate the Akt/mammalian target of rapamycin (mTOR)/p70S6 kinase (S6K) pathway, thereby inhibiting protein synthesis. Therefore, knockdown of PDK1 in healthy mice blocked miR-193b-induced inactivation of the Akt/mTOR/S6K pathway and impairment of muscle growth.
    CONCLUSIONS/INTERPRETATION: Our results identified a previously unrecognised role of miR-193b in muscle function and mass that could be a potential therapeutic target for treating sarcopenia.
    Keywords:  Akt; Muscles atrophy; PDK1; Type 2 diabetes; miR-193b
    DOI:  https://doi.org/10.1007/s00125-021-05616-y
  17. Sci Rep. 2021 Dec 14. 11(1): 23930
    Transcriptomic adaptation during skeletal muscle habituation to eccentric or concentric exercise training.
    Craig R G Willis, Colleen S Deane, Ryan M Ames, Joseph J Bass, Daniel J Wilkinson, Kenneth Smith, Bethan E Phillips, Nathaniel J Szewczyk, Philip J Atherton, Timothy Etheridge.
      Eccentric (ECC) and concentric (CON) contractions induce distinct muscle remodelling patterns that manifest early during exercise training, the causes of which remain unclear. We examined molecular signatures of early contraction mode-specific muscle adaptation via transcriptome-wide network and secretome analyses during 2 weeks of ECC- versus CON-specific (downhill versus uphill running) exercise training (exercise 'habituation'). Despite habituation attenuating total numbers of exercise-induced genes, functional gene-level profiles of untrained ECC or CON were largely unaltered post-habituation. Network analysis revealed 11 ECC-specific modules, including upregulated extracellular matrix and immune profiles plus downregulated mitochondrial pathways following untrained ECC. Of 3 CON-unique modules, 2 were ribosome-related and downregulated post-habituation. Across training, 376 ECC-specific and 110 CON-specific hub genes were identified, plus 45 predicted transcription factors. Secreted factors were enriched in 3 ECC- and/or CON-responsive modules, with all 3 also being under the predicted transcriptional control of SP1 and KLF4. Of 34 candidate myokine hubs, 1 was also predicted to have elevated expression in skeletal muscle versus other tissues: THBS4, of a secretome-enriched module upregulated after untrained ECC. In conclusion, distinct untrained ECC and CON transcriptional responses are dampened after habituation without substantially shifting molecular functional profiles, providing new mechanistic candidates into contraction-mode specific muscle regulation.
    DOI:  https://doi.org/10.1038/s41598-021-03393-7
  18. Neural Regen Res. 2022 Jul;17(7): 1617-1622
    MicroRNA is a potential target for therapies to improve the physiological function of skeletal muscle after trauma.
    Xin-Yi Gu, Bo Jin, Zhi-Dan Qi, Xiao-Feng Yin.
      MicroRNAs can regulate the function of ion channels in many organs. Based on our previous study we propose that miR-142a-39, which is highly expressed in denervated skeletal muscle, might affect cell excitability through similar mechanisms. In this study, we overexpressed or knocked down miR-142a-3p in C2C12 cells using a lentivirus method. After 7 days of differentiation culture, whole-cell currents were recorded. The results showed that overexpression of miR-142a-3p reduced the cell membrane capacitance, increased potassium current density and decreased calcium current density. Knockdown of miR-142a-3p reduced sodium ion channel current density. The results showed that change in miR-142a-3p expression affected the ion channel currents in C2C12 cells, suggesting its possible roles in muscle cell electrophysiology. This study was approved by the Animal Ethics Committee of Peking University in July 2020 (approval No. LA2017128).
    Keywords:  C2C12; denervation; ion channels; miR-142a-3p; microRNA; muscle; patch clamp; potassium; sodium; whole-cell currents
    DOI:  https://doi.org/10.4103/1673-5374.330620
  19. Curr Res Pharmacol Drug Discov. 2021 ;2 100061
    SENP2 is vital for optimal insulin signaling and insulin-stimulated glycogen synthesis in human skeletal muscle cells.
    Jenny Lund, Solveig A Krapf, Medina Sistek, Hege G Bakke, Stefano Bartesaghi, Xiao-Rong Peng, Arild C Rustan, G Hege Thoresen, Eili T Kase.
      Sentrin-specific protease (SENP) 2 has been suggested as a possible novel drug target for the treatment of obesity and type 2 diabetes mellitus after observations of a palmitate-induced increase in SENP2 that lead to increased fatty acid oxidation and improved insulin sensitivity in skeletal muscle cells from mice. However, no precedent research has examined the role of SENP2 in human skeletal muscle cells. In the present work, we have investigated the impact of SENP2 on fatty acid and glucose metabolism as well as insulin sensitivity in human skeletal muscle using cultured primary human myotubes. Acute (4 ​h) oleic acid oxidation was reduced in SENP2-knockdown (SENP2-KD) cells compared to control cells, with no difference in uptake. After prelabeling (24 ​h) with oleic acid, total lipid content and incorporation into triacylglycerol was decreased, while incorporation into other lipids, as well as complete oxidation and β-oxidation was increased in SENP2-KD cells. Basal glucose uptake (i.e., not under insulin-stimulated conditions) was higher in SENP2-KD cells, whereas oxidation was similar to control myotubes. Further, basal glycogen synthesis was not different in SENP2-KD myotubes, but both insulin-stimulated glycogen synthesis and AktSer473 phosphorylation was completely blunted in SENP2-KD cells. In conclusion, SENP2 plays an important role in fatty acid and glucose metabolism in human myotubes. Interestingly, it also appears to have a pivotal role in regulating myotube insulin sensitivity. Future studies should examine the role of SENP2 in regulation of insulin sensitivity in other tissues and in vivo, defining the potential for SENP2 as a drug target.
    Keywords:  Energy metabolism; Insulin sensitivity; Knockdown; Lentivirus; Primary human myotubes; SENP2
    DOI:  https://doi.org/10.1016/j.crphar.2021.100061
  20. Am J Physiol Cell Physiol. 2021 Dec 15.
    ALY688 elicits adiponectin-mimetic signaling and improves insulin action in skeletal muscle cells.
    Hye Kyoung Sung, Patricia L Mitchell, Sean Gross, Andre Marette, Gary Sweeney.
      Adiponectin is well established to mediate many beneficial metabolic effects, and this has stimulated great interest in development and validation of adiponectin receptor agonists as pharmaceutical tools. This study investigated the effects of ALY688, a peptide-based adiponectin receptor agonist, in rat L6 skeletal muscle cells. ALY688 significantly increased phosphorylation of several adiponectin downstream effectors, including AMPK, ACC and p38MAPK, assessed by immunoblotting and immunofluorescence microscopy. Temporal analysis using cells expressing an Akt biosensor demonstrated that ALY688 enhanced insulin sensitivity. This effect was associated with increased insulin-stimulated Akt and IRS-1 phosphorylation. The functional metabolic significance of these signaling effects was examined by measuring glucose uptake in myoblasts stably overexpressing the glucose transporter GLUT4. ALY688 treatment both increased glucose uptake itself and enhanced insulin-stimulated glucose uptake. In the model of high glucose/high insulin (HGHI)-induced insulin resistant cells, both temporal studies using the Akt biosensor as well as immunoblotting assessing Akt and IRS-1 phosphorylation indicated that ALY688 significantly reduced insulin resistance. Importantly, we observed that ALY688 administration to high-fat high sucrose fed mice also improve glucose handling, validating its efficacy in vivo. In summary, these data indicate that ALY688 activates adiponectin signaling pathways in skeletal muscle, leading to improved insulin sensitivity and beneficial metabolic effects.
    Keywords:  Adiponectin; Insulin; Metabolism; Signaling
    DOI:  https://doi.org/10.1152/ajpcell.00603.2020
  21. Curr Res Pharmacol Drug Discov. 2021 ;2 100039
    Chronic treatment with terbutaline increases glucose and oleic acid oxidation and protein synthesis in cultured human myotubes.
    Christine Skagen, Tuula A Nyman, Xiao-Rong Peng, Gavin O'Mahony, Eili Tranheim Kase, Arild Chr Rustan, G Hege Thoresen.
       Objective: In vivo studies have reported several beneficial metabolic effects of β-adrenergic receptor agonist administration in skeletal muscle, including increased glucose uptake, fatty acid metabolism, lipolysis and mitochondrial biogenesis. Although these effects have been widely studied in vivo, the in vitro data are limited to mouse and rat cell lines. Therefore, we sought to discover the effects of the β2-adrenergic receptor agonist terbutaline on metabolism and protein synthesis in human primary skeletal muscle cells.
    Methods: Human cultured myotubes were exposed to terbutaline in various concentrations (0.01-30 ​μM) for 4 or 96 ​h. Thereafter uptake of [14C]deoxy-D-glucose, oxydation of [14C]glucose and [14C]oleic acid were measured. Incorporation of [14C]leucine, gene expression by qPCR and proteomics analyses by mass spectrometry by the STAGE-TIP method were performed after 96 ​h exposure to 1 and 10 ​μM of terbutaline.
    Results: The results showed that 4 ​h treatment with terbutaline in concentrations up to 1 ​μM increased glucose uptake in human myotubes, but also decreased both glucose and oleic acid oxidation along with oleic acid uptake in concentrations of 10-30 ​μM. Moreover, administration of terbutaline for 96 ​h increased glucose uptake (in terbutaline concentrations up to 1 ​μM) and oxidation (1 ​μM), as well as oleic acid oxidation (0.1-30 ​μM), leucine incorporation into cellular protein (1-10 ​μM) and upregulated several pathways related to mitochondrial metabolism (1 ​μM). Data are available via ProteomeXchange with identifier PXD024063.
    Conclusion: These results suggest that β2-adrenergic receptor have direct effects in human skeletal muscle affecting fuel metabolism and net protein synthesis, effects that might be favourable for both type 2 diabetes and muscle wasting disorders.
    Keywords:  Adrenergic receptor (AR), Cyclic AMP (cAMP); Beta adrenergic receptor; Deoxyglucose (DOG), protein-coupled receptor (GPCR); Energy metabolism; Mammalian target of Rapamycin (mTOR), Oleic acid (OA); Mitochondrial metabolism; Myotubes; Oxidation; Protein Kinase A (PKA), Scintillation Proximity Assay (SPA); Type 2 diabetes (T2D), Trichloroacetic acid (TCA)
    DOI:  https://doi.org/10.1016/j.crphar.2021.100039
  22. Am J Physiol Cell Physiol. 2021 Dec 15.
    Extracellular vesicle secretion is tissue-dependent ex vivo and skeletal muscle myofiber extracellular vesicles reach the circulation in vivo.
    Andrea L Estrada, Zackary J Valenti, Gabriella Hehn, Adam J Amorese, Nicholas S Williams, Nicholas P Balestrieri, Clayton Deighan, Christopher P Allen, Espen E Spangenburg, Nicole A Kruh-Garcia, Daniel S Lark.
      Extracellular vesicles (EVs) are biomarkers and modifiers of human disease. EVs secreted by insulin-responsive tissues like skeletal muscle (SkM) and white adipose (WAT) contribute to metabolic health and disease but the relative abundance of EVs from these tissues has not been directly examined. Human Protein Atlas data and directly measuring EV secretion in mouse SkM and WAT using an ex vivo tissue explant model confirmed that SkM tissue secretes more EVs than WAT. Differences in EV secretion between SkM and WAT were not due to SkM contraction but may be explained by differences in tissue metabolic capacity. We next examined how many EVs secreted from SkM tissue ex vivo and in vivo are myofiber-derived. To do this, a SkM myofiber-specific dual fluorescent reporter mouse was created. Spectral flow cytometry revealed that SkM myofibers are a major source of SkM tissue-derived EVs ex vivo and EV immunocapture indicate that ~5% of circulating tetraspanin-positive EVs are derived from SkM myofibers in vivo. Our findings demonstrate that 1) SkM secretes more EVs than WAT, 2) many SkM tissue EVs are derived from SkM myofibers and 3) SkM myofiber-derived EVs reach the circulation in vivo. These findings advance our understanding of EV secretion between metabolically active tissues and provide direct evidence that SkM myofibers secrete EVs that can reach the circulation in vivo.
    Keywords:  Adipose Tissue; Contraction; Extracellular Vesicle; Myofiber; Skeletal Muscle
    DOI:  https://doi.org/10.1152/ajpcell.00580.2020
  23. J Cell Sci. 2021 Dec 16. pii: jcs.259185. [Epub ahead of print]
    Multiple regions of junctin drive interaction with calsequestrin-1 and localization at triads in skeletal muscle.
    Daniela Rossi, Stefania Lorenzini, Enrico Pierantozzi, Filip Van Petegem, David Osamwonuyi Amadsun, Vincenzo Sorrentino.
      Junctin is a transmembrane protein of striated muscles, localized at the junctional sarcoplasmic reticulum (j-SR). It is characterized by a luminal C-terminal tail, through which it functionally interacts with calsequestrin and the ryanodine receptor. Interaction with calsequestrin was ascribed to the presence of stretches of charged amino acids. However, the regions able to bind calsequestrin have not been defined in detail. We report here that, in non-muscle cells, junctin and calsequestrin assemble in long linear regions within the endoplasmic reticulum, mirroring the formation of calsequestrin polymers. In differentiating myotubes, the two proteins co-localize at triads, where they assemble with other j-SR proteins. By performing GST pull-down assays with distinct regions of the junctin tail, we identified two KEKE motifs able to bind calsequestrin. In addition, stretches of charged amino acids downstream these motifs were found to be also able to bind calsequestrin and the ryanodine receptor. Deletion of even one of these regions impaired the ability of junctin to localize at the j-SR, suggesting that interaction with other proteins at this site represents a key element in junctin targeting.
    Keywords:  Excitation-contraction coupling; KEKE; Sarcoplasmic reticulum; Skeletal muscle; Triads
    DOI:  https://doi.org/10.1242/jcs.259185
  24. Front Physiol. 2021 ;12 790034
    Potential Benefits of a Minimal Dose Eccentric Resistance Training Paradigm to Combat Sarcopenia and Age-Related Muscle and Physical Function Deficits in Older Adults.
    Sara A Harper, Brennan J Thompson.
      The ability of older adults to perform activities of daily living is often limited by the ability to generate high mechanical outputs. Therefore, assessing and developing maximal neuromuscular capacity is essential for determining age-related risk for functional decline as well as the effectiveness of therapeutic interventions. Interventions designed to enhance neuromuscular capacities underpinning maximal mechanical outputs could positively impact functional performance in daily life. Unfortunately, < 10% of older adults meet the current resistance training guidelines. It has recently been proposed that a more "minimal dose" RT model may help engage a greater proportion of older adults, so that they may realize the benefits of RT. Eccentric exercise offers some promising qualities for such an approach due to its efficiency in overloading contractions that can induce substantial neuromuscular adaptations. When used in a minimal dose RT paradigm, eccentric-based RT may be a particularly promising approach for older adults that can efficiently improve muscle mass, strength, and functional performance. One approach that may lead to improved neuromuscular function capacities and overall health is through heightened exercise tolerance which would favor greater exercise participation in older adult populations. Therefore, our perspective article will discuss the implications of using a minimal dose, submaximal (i.e., low intensity) multi-joint eccentric resistance training paradigm as a potentially effective, and yet currently underutilized, means to efficiently improve neuromuscular capacities and function for older adults.
    Keywords:  aging; maximal strength; muscle function; resistance training; strength training
    DOI:  https://doi.org/10.3389/fphys.2021.790034
  25. FASEB J. 2022 Jan;36(1): e22088
    Human and mouse muscle transcriptomic analyses identify insulin receptor mRNA downregulation in hyperinsulinemia-associated insulin resistance.
    Haoning Howard Cen, Bahira Hussein, José Diego Botezelli, Su Wang, Jiashuo Aaron Zhang, Nilou Noursadeghi, Niels Jessen, Brian Rodrigues, James A Timmons, James D Johnson.
      Hyperinsulinemia is commonly viewed as a compensatory response to insulin resistance, yet studies have demonstrated that chronically elevated insulin may also drive insulin resistance. The molecular mechanisms underpinning this potentially cyclic process remain poorly defined, especially on a transcriptome-wide level. Transcriptomic meta-analysis in >450 human samples demonstrated that fasting insulin reliably and negatively correlated with INSR mRNA in skeletal muscle. To establish causality and study the direct effects of prolonged exposure to excess insulin in muscle cells, we incubated C2C12 myotubes with elevated insulin for 16 h, followed by 6 h of serum starvation, and established that acute AKT and ERK signaling were attenuated in this model of in vitro hyperinsulinemia. Global RNA-sequencing of cells both before and after nutrient withdrawal highlighted genes in the insulin receptor (INSR) signaling, FOXO signaling, and glucose metabolism pathways indicative of 'hyperinsulinemia' and 'starvation' programs. Consistently, we observed that hyperinsulinemia led to a substantial reduction in Insr gene expression, and subsequently a reduced surface INSR and total INSR protein, both in vitro and in vivo. Bioinformatic modeling combined with RNAi identified SIN3A as a negative regulator of Insr mRNA (and JUND, MAX, and MXI as positive regulators of Irs2 mRNA). Together, our analysis identifies mechanisms which may explain the cyclic processes underlying hyperinsulinemia-induced insulin resistance in muscle, a process directly relevant to the etiology and disease progression of type 2 diabetes.
    Keywords:  SIN3A; hyperinsulinemia; insulin receptor; insulin resistance; insulin signaling
    DOI:  https://doi.org/10.1096/fj.202100497RR
  26. Curr Res Pharmacol Drug Discov. 2021 ;2 100060
    The small molecule SERCA activator CDN1163 increases energy metabolism in human skeletal muscle cells.
    Abel M Mengeste, Jenny Lund, Parmeshwar Katare, Roya Ghobadi, Hege G Bakke, Per Kristian Lunde, Lars Eide, Gavin O' Mahony, Sven Göpel, Xiao-Rong Peng, Eili Tranheim Kase, G Hege Thoresen, Arild C Rustan.
       Background and objective: A number of studies have highlighted muscle-specific mechanisms of thermogenesis involving futile cycling of Ca2+ driven by sarco (endo)plasmic reticulum Ca2+-ATPase (SERCA) and generating heat from ATP hydrolysis to be a promising strategy to counteract obesity and metabolic dysfunction. However, to the best of our knowledge, no experimental studies concerning the metabolic effects of pharmacologically targeting SERCA in human skeletal muscle cells have been reported. Thus, in the present study, we aimed to explore the effects of SERCA-activating compound, CDN1163, on energy metabolism in differentiated human skeletal muscle cells (myotubes).
    Methods: In this study, we used primary myotube cultures derived from muscle biopsies of the musculus vastus lateralis and musculi interspinales from lean, healthy male donors. Energy metabolism in myotubes was studied using radioactive substrates. Oxygen consumption rate was assessed with the Seahorse XF24 bioanalyzer, whereas metabolic genes and protein expressions were determined by qPCR and immunoblotting, respectively.
    Results: Both acute (4 ​h) and chronic (5 days) treatment of myotubes with CDN1163 showed increased uptake and oxidation of glucose, as well as complete fatty acid oxidation in the presence of carbonyl cyanide 4-(trifluromethoxy)phenylhydrazone (FCCP). These effects were supported by measurement of oxygen consumption rate, in which the oxidative spare capacity and maximal respiration were enhanced after CDN1163-treatment. In addition, chronic treatment with CDN1163 improved cellular uptake of oleic acid (OA) and fatty acid β-oxidation. The increased OA metabolism was accompanied by enhanced mRNA-expression of carnitine palmitoyl transferase (CPT) 1B, pyruvate dehydrogenase kinase (PDK) 4, as well as increased AMP-activated protein kinase (AMPK)Thr172 phosphorylation. Moreover, following chronic CDN1163 treatment, the expression levels of stearoyl-CoA desaturase (SCD) 1 was decreased together with de novo lipogenesis from acetic acid and formation of diacylglycerol (DAG) from OA.
    Conclusion: Altogether, these results suggest that SERCA activation by CDN1163 enhances energy metabolism in human myotubes, which might be favourable in relation to disorders that are related to metabolic dysfunction such as obesity and type 2 diabetes mellitus.
    Keywords:  AMPK; AMPK, AMP-activated protein kinase; ASM, acid-soluble metabolites; CE, cholesteryl ester; DAG, diacylglycerol; FA, fatty acid; FCCP, 4-(trifluromethoxy)phenylhydrazone; Glucose metabolism; Lipid metabolism; OA, oleic acid; OCR, oxygen consumption rate; Obesity; SCD1, stearoyl-CoA desaturase 1; SERCA; SERCA, sarco(endo)plasmic reticulum Ca2+-ATPase; Skeletal muscle; T2DM, type 2 diabetes mellitus; Type 2 diabetes
    DOI:  https://doi.org/10.1016/j.crphar.2021.100060
  27. J Appl Physiol (1985). 2021 Dec 16.
    CHOP is Dispensable for Exercise-Induced Increases in GDF15.
    Logan K Townsend, Kyle D Medak, Alyssa J Weber, Hana Dibe, Hesham Shamshoum, David C Wright.
      Growth differentiating factor-15 (GDF15) is expressed, and secreted, from a wide range of tissues and serves as a marker of cellular stress. A key transcriptional regulator of this hormone is the endoplasmic reticulum stress protein, CHOP (C/EBP Homologous Protein). Exercise increases GDF15 levels but the underlying mechanisms of this are not known. To test whether CHOP regulates GDF15 during exercise we used various models of altered ER stress. We examined the effects of acute exercise on circulating GDF15 and GDF15 mRNA expression in liver, triceps skeletal muscle, and epididymal white adipose tissue and examined the GDF15 response to acute exercise in lean and high-fat diet-induced obese mice, sedentary and exercise trained mice, and CHOP deficient mice. We found that obesity augments exercise-induced circulating GDF15 although ER stress markers were similar in lean and obese mice. Exercise-induced GDF15 was increased in trained and sedentary mice that ran at the same relative exercise intensity, despite trained mice being protected against increased markers of ER stress. Finally, exercise-induced increases in GDF15 at the tissue and whole-body level were intact in CHOP deficient mice. Together, these results provide evidence that exercise-induced GDF15 expression and secretion occurs independent of ER stress/CHOP.
    Keywords:  CHOP; ER Stress; Exercise; GDF15; Obesity
    DOI:  https://doi.org/10.1152/japplphysiol.00698.2021
  28. Clin Ther. 2021 Dec 12. pii: S0149-2918(21)00466-5. [Epub ahead of print]
    Resistance Training as Treatment for Sarcopenia: Examining Sex-Related Differences in Physiology and Response.
    Ryan Cheng, Aidan Maloney, Jay Moran, Thomas H Newman, Elizabeth C Gardner.
      Sarcopenia or muscle mass atrophy reportedly occurs in up to 50% of those aged >80 years and is a significant risk factor for functional disability and poor physical performance. Over time, the deterioration in both skeletal muscle quality and composition may compromise functional independence and has been shown to independently increase the risk for falls, fractures, and overall poor health in the elderly population. These are seen most obviously in older women. Given these serious consequences, much effort has been directed toward promoting increased activity and resistance training for muscle maintenance or even muscle regeneration in older adults. The Centers for Disease Control and Prevention states that for all adults ≥65 years of age, weekly aerobic and strength training are vital to healthy aging. Older patients who have not previously participated in strength training may be hesitant about starting a resistance training program and resort to simple and familiar aerobic exercise options such as walking, jogging, or cycling. However, the benefits of strength training are too important to miss: it can improve skeletal muscle metabolic capacity, mitigate effects of aging on functional capacity, maintain bone density, and, most importantly, help individuals maintain a higher quality of life and independence. Due to their increased risk of disability and injury, this opportunity for "exercise as medicine" is particularly important to women and must be encouraged by clinicians. As such, the purpose of this commentary was to highlight known sex-related differences in muscle metabolism and potential benefits of resistance training for elderly patients. A comprehensive understanding of the issues and prevention measures presented here may allow clinicians to better serve their patients, especially older female patients, and, ultimately, alleviate the burden placed on our society by our rapidly aging population.
    Keywords:  elderly; resistance training; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1016/j.clinthera.2021.11.012
  29. Am J Physiol Regul Integr Comp Physiol. 2021 Dec 15.
    Effects of an acute exercise bout in hypoxia on extracellular vesicle release in healthy and prediabetic subjects.
    Geoffrey Warnier, Estelle De Groote, Florian A Britto, Ophélie Delcorte, Joshua P Nederveen, Mats I Nilsson, Christophe E Pierreux, Mark A Tarnopolsky, Louise Deldicque.
       PURPOSE: To investigate exosome-like vesicle (ELV) plasma concentrations and markers of multivesicular body (MVB) biogenesis in skeletal muscle in response to acute exercise.
    METHODS: Seventeen healthy (BMI: 23.5±0.5kg·m-2) and fifteen prediabetic (BMI: 27.3±1.2kg·m-2) men were randomly assigned to two groups performing an acute cycling bout in normoxia or hypoxia (FiO2 14.0%). Venous blood samples were taken before (T0), during (T30) and after (T60) exercise and biopsies from m. vastus lateralis were collected before and after exercise. Plasma ELVs were isolated by size exclusion chromatography, counted by nanoparticle tracking analysis (NTA), and characterized according to international standards, followed by expression analyses of canonical ELV markers in skeletal muscle.
    RESULTS: In the healthy normoxic group, the total number of particles in the plasma increased during exercise from T0 to T30 (+313%) followed by a decrease from T30 to T60 (-53%). In the same group, an increase in TSG101, CD81 and HSP60 protein expression was measured after exercise in plasma ELVs; however, in the prediabetic group, the total number of particles in the plasma was not affected by exercise. The mRNA content of TSG101, ALIX and CD9 were upregulated in skeletal muscle after exercise in normoxia; whereas, CD9 and CD81 were downregulated in hypoxia.
    CONCLUSIONS: ELV plasma abundance increased in response to acute aerobic exercise in healthy subjects in normoxia, but not in prediabetic subjects, nor in hypoxia. Skeletal muscle analyses suggested that this tissue did not likely play a major role of the exercise-induced increase in circulating ELVs.
    Keywords:  ALIX; TSG101; cycling; exosomes; prediabetes
    DOI:  https://doi.org/10.1152/ajpregu.00220.2021
  30. RNA Biol. 2021 Dec 14. 1-11
    Poly C Binding Protein 2 dependent nuclear retention of the utrophin-A mRNA in C2C12 cells.
    Gargi Ghosh, Satyabrata Samui, Santanu Das, Vandana Singh, Doel Pal, Subhanwita Das, Jishu Naskar, Soumya Sinha Roy, Utpal Basu.
      Upregulation of utrophin, the autosomal homologue of dystrophin, can compensate dystrophin deficiency in Duchenne Muscular Dystrophy (DMD) although the therapeutic success is yet to be achieved. The present study has identified Poly (C) binding protein 2 (PCBP2) as a post-transcriptional suppresser for the expression of utrophin-A, the muscle-specific utrophin isoform. This study confirms nuclear retention of utrophin-A mRNA in C2C12 cells, which is mediated by PCBP2. Further investigation demonstrates PCBP2-dependent nuclear retention of follistatin mRNA as well. Its involvement in nuclear retention of mRNA sheds light on a novel function of PCBP2 that makes utrophin-A mRNA less available in cytosol. PCBP2, therefore, may be a target to de-repress utrophin-A expression in DMD.
    Keywords:  DMD; PCBP2; follistatin; nuclear retention; utrophin-A
    DOI:  https://doi.org/10.1080/15476286.2021.2004683
  31. J Mol Cell Cardiol. 2021 Dec 13. pii: S0022-2828(21)00231-5. [Epub ahead of print]
    Hallmarks of exercised heart.
    Yan Qiu, Xue Pan, Yiwen Chen, Junjie Xiao.
      The benefits of exercise in humans on the heart have been well recognized for many years. Long-term endurance exercise training can induce physiologic cardiac hypertrophy with normal or enhanced heart function, and provide protective benefits in preventing heart failure. The heart-specific responses that occur during exercise are complex and highly variable. This review mainly focuses on the current understanding of the structural and functional cardiac adaptations to exercise as well as molecular pathways and signaling proteins responsible for these changes. Here, we summarize eight tentative hallmarks that represent common denominators of the exercised heart. These hallmarks are: cardiomyocyte growth, cardiomyocyte fate reprogramming, angiogenesis and lymphangiogenesis, mitochondrial remodeling, epigenetic alteration, enhanced endothelial function, quiescent cardiac fibroblast, and improved cardiac metabolism. A major challenge is to explore the underlying molecular mechanisms for cardio-protective effects of exercise, and to identify therapeutic targets for heart diseases.
    Keywords:  Cardiac adaptation; Exercise; Hallmarks; Physiologic cardiac hypertrophy
    DOI:  https://doi.org/10.1016/j.yjmcc.2021.12.004
  32. BMC Geriatr. 2021 Dec 15. 21(1): 697
    Do skeletal muscle composition and gene expression as well as acute exercise-induced serum adaptations in older adults depend on fitness status?
    Daniel A Bizjak, Martina Zügel, Uwe Schumann, Mark A Tully, Dhayana Dallmeier, Michael Denkinger, Jürgen M Steinacker.
       BACKGROUND: Inactive physical behavior among the elderly is one risk factor for cardiovascular disease, immobility and increased all-cause mortality. We aimed to answer the question whether or not circulating and skeletal muscle biomarkers are differentially expressed depending on fitness status in a group of elderly individuals.
    METHODS: Twenty-eight elderly individuals (73.36 ± 5.46 years) participated in this exploratory study after participating as part of the multinational SITLESS-clinical trial (implementation of self-management and exercise programs over 16 weeks). A cardiopulmonary exercise test (CPX) and resting skeletal muscle biopsy were performed to determine individual physiological performance capacity. Participants were categorized into a high physical fitness group (HPF) and a low physical fitness group (LPF) depending on peak oxygen uptake (VO2peak). Serum blood samples were taken before (pre) and after (post) CPX and were examined regarding serum BDNF, HSP70, Kynurenine, Irisin and Il-6 concentrations. Skeletal muscle tissue was analyzed by silver staining to determine the myosin heavy chain (MyHC) composition and selected genes by qRT-PCR.
    RESULTS: HPF showed lower body weight and body fat, while skeletal muscle mass and oxygen uptake at the first ventilatory threshold (VO2T1) did not differ between groups. There were positive associations between VO2peak and VO2VT1 in HPF and LPF. MyHC isoform quantification revealed no differences between groups. qRT-PCR showed higher expression of BDNF and BRCA1 in LPF skeletal muscle while there were no differences in other examined genes regarding energy metabolism. Basal serum concentrations of Irisin were higher in HPF compared to LPF with a trend towards higher values in BDNF and HSP70 in HPF. Increases in Il-6 in both groups were observed post.
    CONCLUSIONS: Although no association between muscle composition/VO2peak with fitness status in older people was detected, higher basal Irisin serum levels in HPF revealed slightly beneficial molecular serum and muscle adaptations.
    TRIAL REGISTRATION: ClinicalTrials.gov, NCT02629666 . Registered 19 November 2015.
    Keywords:  Health services for older individuals; Molecular adaptations; Physical fitness; Sedentary behavior; Skeletal muscle
    DOI:  https://doi.org/10.1186/s12877-021-02666-0
  33. Physiol Res. 2021 Nov 30. 70(Suppl 1): S91-S98
    The Severity of Muscle Performance Deterioration in Sarcopenia Correlates With Circulating Muscle Tissue-Specific miRNAs.
    S Valášková, A Gažová, P Vrbová, T Koller, B Šalingova, A Adamičková, N Chomaničová, N Hulajová, J Payer, J Kyselovič.
      Sarcopenia is defined as an age-associated loss of skeletal muscle function and muscle mass and is common in older adults. Sarcopenia as a disease is currently of interest not only to orthopedists and surgeons but also to internists, endocrinologists, rheumatologists, cardiologists, diabetologists, gynaecologists, geriatricians and paediatricians. In cooperation with the 5th Internal Medicine Clinic, we, as a unit of clinical research, aimed to describe a sarcopenic specific miRNA expression profile for disease diagnostics and classification of the severity of muscle performance deterioration. This study included a total of 80 patients (age 55-86 years) hospitalized at the V. Internal medicine clinic of LFUK and UNB with different severity of muscle performance deterioration. The study participants were evaluated and classified according to short physical performance battery score (SPPB). In this study, we investigated the role of circulating miRNAs in sarcopenia in the elderly. We hypothesized that sarcopenia effects the expression of muscle tissue-specific miRNAs (MyomiRNAs), which could be potentially reflected in the blood plasma miRNA expression profile. The expression of specific circulating miRNAs in patients with different muscle performances was analyzed. Patients' blood plasma was evaluated for the expression of myomiRNAs: miRNA-29a, miRNA-29b, miRNA-1, miRNA-133a, miRNA-133b, miRNA-206, miRNA-208b and miRNA-499, and the data were correlated with diagnostic indicators of the disease. We showed a specific sarcopenia miRNA profile that could be considered a possible biomarker for the disease. Patients with low muscle performance showed increased miRNA-1, miRNA-29a and miRNA-29b expression and decreased for the miRNA-206, miRNA-133a, miRNA-133b, miRNA-208b and miRNA-499 expression. We show that the severity of muscle performance deterioration in sarcopenia correlates with specific miRNA expression. We also propose the profile of miRNAs expression in blood plasma as a specific biomarker for sarcopenia diagnostics. Future clinical studies will be necessary to eventually naturally have to elucidate the underlined molecular mechanism responsible for specific miRNAs expression in sarcopenia pathology and progression of the disease.
  34. Front Physiol. 2021 ;12 752347
    Differential Autophagy Response in Men and Women After Muscle Damage.
    Hui-Ying Luk, Casey Appell, Danielle E Levitt, Nigel C Jiwan, Jakob L Vingren.
      Following muscle damage, autophagy is crucial for muscle regeneration. Hormones (e.g., testosterone, cortisol) regulate this process and sex differences in autophagic flux exist in the basal state. However, to date, no study has examined the effect of a transient hormonal response following eccentric exercise-induced muscle damage (EE) between untrained young men and women. Untrained men (n = 8, 22 ± 3 years) and women (n = 8, 19 ± 1 year) completed two sessions of 80 unilateral maximal eccentric knee extensions followed by either upper body resistance exercise (RE; designed to induce a hormonal response; EE + RE) or a time-matched rest period (20 min; EE + REST). Vastus lateralis biopsy samples were collected before (BL), and 12 h, and 24 h after RE/REST. Gene and protein expression levels of selective markers for autophagic initiation signaling, phagophore initiation, and elongation/sequestration were determined. Basal markers of autophagy were not different between sexes. For EE + RE, although initiation signaling (FOXO3) and autophagy-promoting (BECN1) genes were greater (p < 0.0001; 12.4-fold, p = 0.0010; 10.5-fold, respectively) for women than men, autophagic flux (LC3-II/LC3-I protein ratio) did not change for women and was lower (p < 0.0001 3.0-fold) than men. Furthermore, regardless of hormonal changes, LC3-I and LC3-II protein content decreased (p = 0.0090; 0.547-fold, p = 0.0410; 0.307-fold, respectively) for men suggesting increased LC3-I lipidation and autophagosome degradation whereas LC3-I protein content increased (p = 0.0360; 1.485-fold) for women suggesting decreased LC3-I lipidation. Collectively, our findings demonstrated basal autophagy was not different between men and women, did not change after EE alone, and was promoted with the acute hormonal increase after RE only in men but not in women. Thus, the autophagy response to moderate muscle damage is promoted by RE-induced hormonal changes in men only.
    Keywords:  LC3-II/LC3-I ratio; cortisol; growth hormone; macroautophagy; sex dimorphism
    DOI:  https://doi.org/10.3389/fphys.2021.752347
  35. Nat Commun. 2021 Dec 14. 12(1): 7256
    Paracrine FGFs target skeletal muscle to exert potent anti-hyperglycemic effects.
    Lei Ying, Luyao Wang, Kaiwen Guo, Yushu Hou, Na Li, Shuyi Wang, Xingfeng Liu, Qijin Zhao, Jie Zhou, Longwei Zhao, Jianlou Niu, Chuchu Chen, Lintao Song, Shaocong Hou, Lijuan Kong, Xiaokun Li, Jun Ren, Pingping Li, Moosa Mohammadi, Zhifeng Huang.
      Several members of the FGF family have been identified as potential regulators of glucose homeostasis. We previously reported that a low threshold of FGF-induced FGF receptor 1c (FGFR1c) dimerization and activity is sufficient to evoke a glucose lowering activity. We therefore reasoned that ligand identity may not matter, and that besides paracrine FGF1 and endocrine FGF21, other cognate paracrine FGFs of FGFR1c might possess such activity. Indeed, via a side-by-side testing of multiple cognate FGFs of FGFR1c in diabetic mice we identified the paracrine FGF4 as a potent anti-hyperglycemic FGF. Importantly, we found that like FGF1, the paracrine FGF4 is also more efficacious than endocrine FGF21 in lowering blood glucose. We show that paracrine FGF4 and FGF1 exert their superior glycemic control by targeting skeletal muscle, which expresses copious FGFR1c but lacks β-klotho (KLB), an obligatory FGF21 co-receptor. Mechanistically, both FGF4 and FGF1 upregulate GLUT4 cell surface abundance in skeletal muscle in an AMPKα-dependent but insulin-independent manner. Chronic treatment with rFGF4 improves insulin resistance and suppresses adipose macrophage infiltration and inflammation. Notably, unlike FGF1 (a pan-FGFR ligand), FGF4, which has more restricted FGFR1c binding specificity, has no apparent effect on food intake. The potent anti-hyperglycemic and anti-inflammatory properties of FGF4 testify to its promising potential for use in the treatment of T2D and related metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-021-27584-y
  36. Sci Adv. 2021 Dec 17. 7(51): eabl4988
    Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance.
    Chrysovalantou E Xirouchaki, Yaoyao Jia, Meagan J McGrath, Spencer Greatorex, Melanie Tran, Troy L Merry, Dawn Hong, Matthew J Eramo, Sophie C Broome, Jonathan S T Woodhead, Randall F D'souza, Jenny Gallagher, Ekaterina Salimova, Cheng Huang, Ralf B Schittenhelm, Junichi Sadoshima, Matthew J Watt, Christina A Mitchell, Tony Tiganis.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/sciadv.abl4988
  37. Biol Open. 2021 Dec 13. pii: bio.058666. [Epub ahead of print]
    The Abl-interactor Abi suppresses the function of the BRAG2 GEF family member Schizo.
    Stefanie Lübke, Carina Braukmann, Karl-Heinz Rexer, Lubjinka Cigoja, Pratiti Rout, Susanne F Önel.
      Guanine nucleotide exchange factors (GEF) of the BRAG subfamily activate small Arf GTPases, which are pivotal regulators of intracellular membrane traffic and actin dynamics. Consequently, BRAG proteins have been implicated to regulate the surface levels of adhesive and signaling receptors. However, not much is known about the mechanism leading to the regulation of these surface proteins. In this study we found that the Drosophila BRAG GEF Schizo interacts physically with the Abl-interactor (Abi). schizo mutants display severe defects in myoblast fusion during syncytial muscle formation and show increased amounts of the cell adhesion protein N-cadherin. We demonstrate that the schizo myoblast fusion phenotype can be rescued by the expression of the Schizo GEF (Sec7) and membrane-binding (pleckstrin homology) domain. Furthermore, the expression of the Sec7-PH domain in a wild-type background decreases the amounts of N-cadherin and impairs myoblast fusion. These findings support the notion that the Sec7-PH domain serves as a constitutive-active form of Schizo. Using a yeast-two hybrid assay, we show that the SH3 domain of Abi interacts with the N-terminal region of Schizo. This region is also able to bind to the cytodomain of the cell adhesion molecule N-cadherin. To shed light on the function of Schizo and Abi in N-cadherin removal, we employed epistasis experiments in different developmental contexts of Drosophila. These studies point towards a new model for the regulation of Schizo. We propose that the binding of Abi to the N-terminal part of Schizo antagonizes Schizo function to inhibit N-cadherin removal.
    Keywords:  Axon guidance; Graf-1; Myoblast fusion; N-Cadherin; Sec7; Slit
    DOI:  https://doi.org/10.1242/bio.058666
  38. Muscle Nerve. 2021 Dec 16.
    Characterization of patients with Becker muscular dystrophy by histology, magnetic resonance imaging, function, and strength assessments.
    Giacomo P Comi, Erik H Niks, Claudia M Cinnante, Hermien E Kan, Krista Vandenborne, Rebecca J Willcocks, Daniele Velardo, Michela Ripolone, Jules J van Benthem, Nienke M van de Velde, Simone Nava, Laura Ambrosoli, Sara Cazzaniga, Paolo U Bettica.
       INTRODUCTION/AIMS: Becker muscular dystrophy (BMD) is characterized by variable disease severity and progression, prompting the identification of biomarkers for clinical trials. We used data from an ongoing Phase II study to provide a comprehensive characterization of a cohort of patients with BMD, and to assess correlations between histological and magnetic resonance imaging (MRI) markers with muscle function and strength.
    METHODS: Eligible patients were ambulatory males with BMD aged 18-65 years (200-450m on 6 minute walk test). The following were measured: function tests, strength, fat-fraction quantification using chemical shift-encoded MRI (whole thigh and quadriceps), and fibrosis and muscle fiber area (MFA) of the brachial biceps.
    RESULTS: Of 70 patients screened, 51 entered the study. There was substantial heterogeneity between patients in muscle morphology (histology and MRI), with high fat replacement. Total fibrosis correlated significantly and mostly moderately with all functional endpoints, including both upper arm strength assessments (left and right elbow flexion Rho -0.574 and -0.588, respectively [both p<0.0001]), as did MRI fat fraction (whole thigh and quadriceps), e.g., with four stair climb velocity -0.554 and -0.550, respectively (both p<0.0001). Total fibrosis correlated significantly and moderately with both MRI fat fraction assessments (0.500 [p=0.0003] and 0.423 [0.0024], respectively).
    DISCUSSION: In this BMD cohort, micro- and macroscopic morphological muscle parameters correlated moderately with each other and with functional parameters, potentially supporting the use of MRI fat fraction and histology as surrogate outcome measures in patients with BMD, although additional research is required to validate this. This article is protected by copyright. All rights reserved.
    Keywords:  Becker muscular dystrophy; correlation; function; histology; magnetic resonance imaging
    DOI:  https://doi.org/10.1002/mus.27475
  39. BMC Geriatr. 2021 Dec 15. 21(1): 708
    Effects of different exercise training modes on muscle strength and physical performance in older people with sarcopenia: a systematic review and meta-analysis.
    Linqian Lu, Lin Mao, Yuwei Feng, Barbara E Ainsworth, Yu Liu, Nan Chen.
       OBJECTIVE: We conducted a systematic review and meta-analysis to clarify the effects of different exercise modes (resistance training [RT], whole body vibration training [WBVT], and mixed training [MT, resistance training combined with other exercises such as balance, endurance and aerobic training]) on muscle strength (knee extension strength [KES]) and physical performance (Timed Up and Go [TUG], gait speed [GS] and the Chair Stand [CS]) in older people with sarcopenia.
    METHOD: All studies published from January 2010 to March 2021 on the effects of exercise training in older people with sarcopenia were retrieved from 6 electronic databases: Pubmed, Cochrane Library, Embase, Web of Science, the China National Knowledge Infrastructure (CNKI), and Wanfang Database. Two researchers independently extracted and evaluated studies that met inclusion and exclusion criteria. Pooled analyses for pre- and post- outcome measurements were performed using Review Manager 5.4 with standardized mean differences (SMDs) and fixed-effect models.
    RESULT: Twenty-six studies (25 randomized controlled trails [RCTs] and one non-randomized controlled trail) were included in this study with 1191 older people with sarcopenia (mean age 60.6 ± 2.3 to 89.5 ± 4.4). Compared with a control group, RT and MT significantly improved KES (RT, SMD = 1.36, 95% confidence intervals [95% CI]: 0.71 to 2.02, p < 0.0001, I2 = 72%; MT, SMD = 0.62, 95% CI: 0.29 to 0.95, p = 0.0002, I2 = 56%) and GS (RT, SMD = 2.01, 95% CI: 1.04 to 2.97, p < 0.0001, I2 = 84%; MT, SMD = 0.69, 95% CI: 0.29 to 1.09, p = 0.008, I2 = 81%). WBVT showed no changes in KES (SMD = 0.65, 95% CI: - 0.02 to 1.31, p = 0.06, I2 = 80%) or GS (SMD = 0.12, 95% CI: - 0.15 to 0.39, p = 0.38, I2 = 0%). TUG times were significantly improved with all exercise training modes (SMD = -0.66, 95% CI: - 0.94 to - 0.38, p < 0.00001, I2 = 60%). There were no changes in CS times with any of the exercise training modes (SMD = 0.11, 95% CI: - 0.36 to 0.57, p = 0.65, I2 = 87%).
    CONCLUSIONS: In older people with sarcopenia, KES and GS can be improved by RT and MT, but not by WBVT. All three training modes improved TUG times, but not improved CS times.
    Keywords:  Mixed training; Muscle strength; Physical performance; Resistance training; Sarcopenia; Whole body vibration training
    DOI:  https://doi.org/10.1186/s12877-021-02642-8
  40. JPEN J Parenter Enteral Nutr. 2021 Nov;45(S2): 16-25
    Nutrition challenges of cancer cachexia.
    Omnia U Gaafer, Teresa A Zimmers.
      Cancer cachexia, or progressive weight loss, often despite adequate nutrition contributes greatly to cancer morbidity and mortality. Cachexia is metabolically distinct from starvation or protein malnutrition, although many patients with cancer and cachexia exhibit lowered appetite and food consumption. Tumors affect neural mechanisms that regulate appetite and energy expenditure, while promoting wasting of peripheral tissues via catabolism of cardiac and skeletal muscle, adipose, and bone. These multimodal actions of tumors on the host suggest a need for multimodal interventions. However, multiple recent consensus guidelines for management of cancer cachexia differ in treatment recommendations, highlighting the lack of effective, available therapies. Challenges to defining appropriate nutrition or other interventions for cancer cachexia include lack of consensus on definitions, low strength of evidence from clinical trials, and a scarcity of robust, rigorous, and mechanistic studies. However, efforts to diagnose, stage, and monitor cachexia are increasing along with clinical trial activity. Furthermore, preclinical models for cancer cachexia are growing more sophisticated, encompassing a greater number of tumor types in organ-appropriate contexts and for metastatic disease to model the clinical condition more accurately. It is expected that continued growth, investment, and coordination of research in this topic will ultimately yield robust biomarkers, clinically useful classification and staging algorithms, targetable pathways, pivotal clinical trials, and ultimately, cures. Here, we provide an overview of the clinical and scientific knowledge and its limitations around cancer cachexia.
    Keywords:  animal models; anorexia; appetite; cachexia; cancer; malnutrition; nutrition
    DOI:  https://doi.org/10.1002/jpen.2287
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