bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2022‒09‒25
39 papers selected by
Anna Vainshtein
Craft Science Inc.
  1. Time for Exercise? Exercise and Its Influence on the Skeletal Muscle Clock.
  2. Characterization of cellular senescence in aging skeletal muscle.
  3. Immunometabolism of macrophages regulates skeletal muscle regeneration.
  4. Skeletal Muscle Dysfunction in Experimental Pulmonary Hypertension.
  5. Immunofluorescence Labeling of Skeletal Muscle in Development, Regeneration, and Disease.
  6. A Review of free fatty acid-induced cell signaling, angiopoietin-like protein 4, and skeletal muscle differentiation.
  7. Multi-transcriptome analysis following an acute skeletal muscle growth stimulus yields tools for discerning global and MYC regulatory networks.
  8. PD-1 Alleviates Cisplatin-Induced Muscle Atrophy by Regulating Inflammation and Oxidative Stress.
  9. Ketogenic Diets and Mitochondrial Function: Benefits for Aging but not for Athletes.
  10. A Mitofusin 2 - Hif1α axis sets a maturation checkpoint in regenerating skeletal muscle.
  11. Multiscale engineered human skeletal muscles with perfusable vasculature and microvascular network recapitulating the fluid compartments.
  12. Inflammation: Roles in Skeletal Muscle Atrophy.
  13. Interrelated but not Time-aligned Response in Myogenic Regulatory Factors Demethylation and mRNA Expression after Divergent Exercise Bouts.
  14. Ginsenoside Rd ameliorates muscle wasting by suppressing the signal transducer and activator of transcription 3 pathway.
  15. BAG3 Attenuates Ischemia-Induced Skeletal Muscle Necroptosis in Diabetic Experimental Peripheral Artery Disease.
  16. Transcriptomic profiles of muscular dystrophy with myositis (mdm) in extensor digitorum longus, psoas, and soleus muscles from mice.
  17. Skeletal Muscle Mitochondrial and Perilipin Content in a Cohort of Obese Subjects Undergoing Moderate and High Intensity Training.
  18. Muscle contractile exercise through a belt electrode device prevents myofiber atrophy, muscle contracture, and muscular pain in immobilized rat gastrocnemius muscle.
  19. Myofibrillar Lattice Remodeling Is a Structural Cytoskeletal Predictor of Diaphragm Muscle Weakness in a Fibrotic mdx (mdx Cmah-/-) Model.
  20. Nerve-dependent distribution of subsynaptic type 1 inositol 1,4,5-trisphosphate receptor at the neuromuscular junction.
  21. Estrogen regulation of myokines that enhance osteoclast differentiation and activity.
  22. The Effect of Uridine on the State of Skeletal Muscles and the Functioning of Mitochondria in Duchenne Dystrophy.
  23. Impaired fatigue resistance, sarcoplasmic reticulum function, and mitochondrial activity in soleus muscle of db/db mice.
  24. Inducible Heat Shock Protein 70 Levels in Patients and the mdx Mouse Affirm Regulation during Skeletal Muscle Regeneration in Muscular Dystrophy.
  25. A Novel Muscle Atrophy Mechanism: Myocyte Degeneration Due to Intracellular Iron Deprivation.
  26. The impact of different exercise protocols on rat soleus muscle reinnervation and recovery following peripheral nerve lesion and regeneration.
  27. Effects of mutant lamins on nucleo-cytoskeletal coupling in Drosophila models of LMNA muscular dystrophy.
  28. Bile Acids Induce Alterations in Mitochondrial Function in Skeletal Muscle Fibers.
  29. Single nuclei transcriptomics of muscle reveals intra-muscular cell dynamics linked to dystrophin loss and rescue.
  30. SMN controls neuromuscular junction integrity through U7 snRNP.
  31. Excitation-contraction coupling in mammalian skeletal muscle: Blending old and last-decade research.
  32. Stretching muscle cells induces transcriptional and splicing transitions and changes in SR proteins.
  33. Role of the Gut Microbiome in Skeletal Muscle Physiology and Pathophysiology.
  34. Lipoxin A4 attenuated dexamethasone-induced muscle atrophy via activation of PGC-1α/Nrf2/TFAM pathway.
  35. Semirational bioengineering of AAV vectors with increased potency and specificity for systemic gene therapy of muscle disorders.
  36. FOXO1 is downregulated in obese mice subjected to short-term strength training.
  37. Gain-of-Function Dynamin-2 Mutations Linked to Centronuclear Myopathy Impair Ca2+-Induced Exocytosis in Human Myoblasts.
  38. RNA binding motif protein 3 (RBM3) promotes protein kinase B (AKT) activation to enhance glucose metabolism and reduce apoptosis in skeletal muscle of mice under acute cold exposure.
  39. Skeletal Muscle Manifestations and Creatine Kinase in COVID-19.
  1. J Biol Rhythms. 2022 Sep 21. 7487304221122662
    Time for Exercise? Exercise and Its Influence on the Skeletal Muscle Clock.
    Ryan A Martin, Karyn A Esser.
      Circadian rhythms drive our daily behaviors to coincide with the earth's rotation on an approximate 24-h cycle. The circadian clock mechanism present in nearly every cell is responsible for our circadian rhythms and is comprised of a transcriptional-translational feedback loop in mammals. The central clock resides in the hypothalamus responding to external light cues, whereas peripheral clocks receive signals from the central clock and are also sensitive to cues from feeding and activity. Of the peripheral clocks, the skeletal muscle clock is particularly sensitive to exercise which has shown to be an important time-cue with the ability to influence and adjust the muscle clock phase in response to exercise timing. Since the skeletal muscle clock is also involved in the expression of tissue-specific gene expression-including glucoregulatory genes-this might suggest a role for exercise timing as a therapeutic strategy in metabolic diseases, like type 2 diabetes. Notably, those with type 2 diabetes have accompanied disruptions in their skeletal muscle clock mechanism which may also be related to the increased risk of type 2 diabetes seen among shift workers. Therefore, the direct influence of exercise on the skeletal muscle clock might support the use of exercise timing to provide disease-mitigating effects. Here, we highlight the potential use of time-of-day exercise as a chronotherapeutic tool within circadian medicine to improve the metabolic profile of type 2 diabetes and support long-term glycemic control, potentially working through the skeletal muscle clock and circadian physiology.
    Keywords:  circadian rhythm; exercise; metabolism; muscle clock; skeletal muscle
    DOI:  https://doi.org/10.1177/07487304221122662
  2. Nat Aging. 2022 Jul;2(7): 601-615
    Characterization of cellular senescence in aging skeletal muscle.
    Xu Zhang, Leena Habiballa, Zaira Aversa, Yan Er Ng, Ayumi E Sakamoto, Davis A Englund, Vesselina M Pearsall, Thomas A White, Matthew M Robinson, Donato A Rivas, Surendra Dasari, Adam J Hruby, Anthony B Lagnado, Sarah K Jachim, Antoneta Granic, Avan A Sayer, Diana Jurk, Ian R Lanza, Sundeep Khosla, Roger A Fielding, K Sreekumaran Nair, Marissa J Schafer, João F Passos, Nathan K LeBrasseur.
      Senescence is a cell fate that contributes to multiple aging-related pathologies. Despite profound age-associated changes in skeletal muscle (SkM), whether its constituent cells are prone to senesce has not been methodically examined. Herein, using single cell and bulk RNA-sequencing and complementary imaging methods on SkM of young and old mice, we demonstrate that a subpopulation of old fibroadipogenic progenitors highly expresses p16 Ink4a together with multiple senescence-related genes and, concomitantly, exhibits DNA damage and chromatin reorganization. Through analysis of isolated myofibers, we also detail a senescence phenotype within a subset of old cells, governed instead by p2 Cip1 . Administration of a senotherapeutic intervention to old mice countered age-related molecular and morphological changes and improved SkM strength. Finally, we found that the senescence phenotype is conserved in SkM from older humans. Collectively, our data provide compelling evidence for cellular senescence as a hallmark and potentially tractable mediator of SkM aging.
    DOI:  https://doi.org/10.1038/s43587-022-00250-8
  3. Front Cell Dev Biol. 2022 ;10 948819
    Immunometabolism of macrophages regulates skeletal muscle regeneration.
    Yu-Fan Chen, Chien-Wei Lee, Hao-Hsiang Wu, Wei-Ting Lin, Oscar K Lee.
      Sarcopenia is an age-related progressive loss of skeletal muscle mass, quality, and strength disease. In addition, sarcopenia is tightly correlated with age-associated pathologies, such as sarcopenic obesity and osteoporosis. Further understanding of disease mechanisms and the therapeutic strategies in muscle regeneration requires a deeper knowledge of the interaction of skeletal muscle and other cells in the muscle tissue. Skeletal muscle regeneration is a complex process that requires a series of highly coordinated events involving communication between muscle stem cells and niche cells, such as muscle fibro/adipogenic progenitors and macrophages. Macrophages play a critical role in tissue regeneration and the maintenance of muscle homeostasis by producing growth factors and cytokines that regulate muscle stem cells and myofibroblast activation. Furthermore, the aging-related immune dysregulation associated with the release of trophic factors and the polarization in macrophages transiently affect the inflammatory phase and impair muscle regeneration. In this review, we focus on the role and regulation of macrophages in skeletal muscle regeneration and homeostasis. The aim of this review is to highlight the important roles of macrophages as a therapeutic target in age-related sarcopenia and the increasing understanding of how macrophages are regulated will help to advance skeletal muscle regeneration.
    Keywords:  macrophages; metabolism; muscle regeneration; muscle stem cells; sarcopenia
    DOI:  https://doi.org/10.3389/fcell.2022.948819
  4. Int J Mol Sci. 2022 Sep 18. pii: 10912. [Epub ahead of print]23(18):
    Skeletal Muscle Dysfunction in Experimental Pulmonary Hypertension.
    Kosmas Kosmas, Zoe Michael, Aimilia Eirini Papathanasiou, Fotios Spyropoulos, Elio Adib, Ravi Jasuja, Helen Christou.
      Pulmonary arterial hypertension (PAH) is a serious, progressive, and often fatal disease that is in urgent need of improved therapies that treat it. One of the remaining therapeutic challenges is the increasingly recognized skeletal muscle dysfunction that interferes with exercise tolerance. Here we report that in the adult rat Sugen/hypoxia (SU/Hx) model of severe pulmonary hypertension (PH), there is highly significant, almost 50%, decrease in exercise endurance, and this is associated with a 25% increase in the abundance of type II muscle fiber markers, thick sarcomeric aggregates and an increase in the levels of FoxO1 in the soleus (a predominantly type I fiber muscle), with additional alterations in the transcriptomic profiles of the diaphragm (a mixed fiber muscle) and the extensor digitorum longus (a predominantly Type II fiber muscle). In addition, soleus atrophy may contribute to impaired exercise endurance. Studies in L6 rat myoblasts have showed that myotube differentiation is associated with increased FoxO1 levels and type II fiber markers, while the inhibition of FoxO1 leads to increased type I fiber markers. We conclude that the formation of aggregates and a FoxO1-mediated shift in the skeletal muscle fiber-type specification may underlie skeletal muscle dysfunction in an experimental study of PH.
    Keywords:  FoxO1; PAH; skeletal muscle; type II fibers
    DOI:  https://doi.org/10.3390/ijms231810912
  5. Methods Mol Biol. 2023 ;2566 113-132
    Immunofluorescence Labeling of Skeletal Muscle in Development, Regeneration, and Disease.
    Marie E Esper, Kasun Kodippili, Michael A Rudnicki.
      Skeletal muscle is composed of long multinucleated cells, termed myofibers, that are formed through the activation and differentiation of resident muscle stem cells, called satellite cells. In healthy individuals, skeletal muscle enables voluntary locomotion while also playing a role in energy metabolism and thermoregulation. As skeletal muscle is integral to everyday processes, perturbations to skeletal muscle function can have devastating consequences. Here we describe an integral tool in biomedical research of skeletal muscle regeneration and disease, the immunofluorescence staining of myogenic cells. We highlight useful techniques for immunostaining myogenic cells, and we list validated antibodies for the staining of muscle proteins across different species and multiple developmental time points. This includes methods for unmasking antigens following formaldehyde fixation (using myosin heavy chain staining as an example) and practices for preserving endogenous fluorescent proteins by cardiac perfusion fixation.
    Keywords:  Antibodies; Differentiation; Heat-induced antigen retrieval; Immunofluorescence; Immunohistochemistry; Muscle stem cell; Myogenesis; Myosin heavy chain; Pax7; Regeneration; Satellite sell; Skeletal muscle
    DOI:  https://doi.org/10.1007/978-1-0716-2675-7_9
  6. Front Physiol. 2022 ;13 987977
    A Review of free fatty acid-induced cell signaling, angiopoietin-like protein 4, and skeletal muscle differentiation.
    Yura Son, Chad M Paton.
      Postnatal skeletal muscle differentiation from quiescent satellite cells is a highly regulated process, although our understanding of the contribution of nutritional factors in myogenesis is limited. Free fatty acids (FFAs) are known to cause detrimental effects to differentiated skeletal muscle cells by increasing oxidative stress which leads to muscle wasting and insulin resistance in skeletal muscle. In addition, FFAs are thought to act as inhibitors of skeletal muscle differentiation. However, the precise molecular mechanisms underlying the effects of FFAs on skeletal muscle differentiation remains to be elucidated. There is a clear relationship between dietary FFAs and their ability to suppress myogenesis and we propose the hypothesis that the FFA-mediated increase in angiopoietin-like protein 4 (ANGPTL4) may play a role in the inhibition of differentiation. This review discusses the role of FFAs in skeletal muscle differentiation to-date and proposes potential mechanisms of FFA-induced ANGPTL4 mediated inhibition of skeletal muscle differentiation.
    Keywords:  ANGPTL4; angiopoietin-like 4; differentiation; lipid metabolism (fatty acids; myogenesis
    DOI:  https://doi.org/10.3389/fphys.2022.987977
  7. J Biol Chem. 2022 Sep 20. pii: S0021-9258(22)00958-9. [Epub ahead of print] 102515
    Multi-transcriptome analysis following an acute skeletal muscle growth stimulus yields tools for discerning global and MYC regulatory networks.
    Kevin A Murach, Zhengye Liu, Baptiste Jude, Vandre C Figueiredo, Yuan Wen, Sabin Khadgi, Seongkyun Lim, Francielly Morena da Silva, Nicholas P Greene, Johanna T Lanner, John J McCarthy, Ivan J Vechetti, Ferdinand von Walden.
      Myc is a powerful transcription factor implicated in epigenetic reprogramming, cellular plasticity, and rapid growth as well as tumorigenesis. Cancer in skeletal muscle is extremely rare despite marked and sustained Myc induction during loading-induced hypertrophy. Here, we investigated global, actively transcribed, stable, and myonucleus-specific transcriptomes following an acute hypertrophic stimulus in mouse plantaris. With these datasets we define global and Myc-specific dynamics at the onset of mechanical overload-induced muscle fiber growth. Data collation across analyses reveals an under-appreciated role for the muscle fiber in extracellular matrix remodeling during adaptation, along with the contribution of mRNA stability to epigenetic-related transcript levels in muscle. We also identify Runx1 and Ankrd1 (Marp1) as abundant myonucleus-enriched loading-induced genes. We observed that a strong induction of cell cycle regulators including Myc occurs with mechanical overload in myonuclei. Additionally, in vivo Myc-controlled gene expression in the plantaris was defined using a genetic muscle fiber-specific doxycycline-inducible Myc-overexpression model. We determined Myc is implicated in numerous aspects of gene expression during early-phase muscle fiber growth. Specifically, brief induction of Myc protein in muscle represses Reverbα, Reverbβ, and Myh2 while increasing Rpl3, recapitulating gene expression in myonuclei during acute overload. Experimental, comparative, and in silico analyses place Myc at the center of a stable and actively transcribed, loading-responsive, muscle fiber-localized regulatory hub. Collectively, our experiments are a roadmap for understanding global and Myc-mediated transcriptional networks that regulate rapid remodeling in post-mitotic cells. We provide open webtools for exploring the five RNA-sequencing datasets as a resource to the field.
    Keywords:  5-Ethenyl uridine; Ankrd1; Gene Transcription; Muscle Hypertrophy; Myonuclei; Myosin; Rpl3; Runx1; Transcriptomics; Warburg Effect
    DOI:  https://doi.org/10.1016/j.jbc.2022.102515
  8. Antioxidants (Basel). 2022 Sep 18. pii: 1839. [Epub ahead of print]11(9):
    PD-1 Alleviates Cisplatin-Induced Muscle Atrophy by Regulating Inflammation and Oxidative Stress.
    Xiaoguang Liu, Miaomiao Xu, Yang Yu, Yingjie Chen, Xinyu Weng, Lin Zhu.
      Skeletal muscle atrophy is an important characteristic of cachexia, which can be induced by chemotherapy and significantly contributes to functional muscle impairment. Inflammation and oxidative stress are believed to play important roles in the muscle atrophy observed in cachexia, but whether programmed cell death protein 1 (PD-1) is affected by this condition remains unclear. PD-1 is a membrane protein that is expressed on the surface of many immune cells and plays an important role in adaptive immune responses and autoimmunity. Thus, we investigated the role and underlying mechanism of PD-1 in cisplatin-induced muscle atrophy in mice. We found that PD-1 knockout dramatically contributed to skeletal muscle atrophy. Mechanistically, we found that E3 ubiquitin-protein ligases were significantly increased in PD-1 knockout mice after cisplatin treatment. In addition, we found that PD-1 knockout significantly exacerbated cisplatin-induced skeletal muscle inflammation and oxidative stress. Moreover, we found that there were significant increases in ferroptosis-related and autophagy-related genes in PD-1 knockout mice after cisplatin treatment. These data indicate that PD-1 plays an important role in cisplatin-induced skeletal muscle atrophy.
    Keywords:  atrophy; inflammation; oxidative stress; skeletal muscle
    DOI:  https://doi.org/10.3390/antiox11091839
  9. Exerc Sport Sci Rev. 2022 Sep 16.
    Ketogenic Diets and Mitochondrial Function: Benefits for Aging but not for Athletes.
    Suraj J Pathak, Keith Baar.
      ABSTRACT: As humans age, we lose skeletal muscle mass, even in the absence of disease (sarcopenia), increasing the risk of death. Low mitochondrial mass and activity contributes to sarcopenia. It is our hypothesis that, a ketogenic diet improves skeletal muscle mitochondrial mass and function when they have declined due to aging or disease, but not in athletes where mitochondrial quality is high.
    DOI:  https://doi.org/10.1249/JES.0000000000000307
  10. J Clin Invest. 2022 Sep 20. pii: e161638. [Epub ahead of print]
    A Mitofusin 2 - Hif1α axis sets a maturation checkpoint in regenerating skeletal muscle.
    Xun Wang, Yuemeng Jia, Jiawei Zhao, Nicholas P Lesner, Cameron J Menezes, Spencer D Shelton, Siva Sai Krishna Venigalla, Jian Xu, Chunyu Cai, Prashant Mishra.
      A fundamental issue in regenerative medicine is whether there exist endogenous regulatory mechanisms that limit the speed and efficiency of the repair process. We report the existence of a maturation checkpoint during muscle regeneration which pauses myofibers at a neonatal stage. This checkpoint is regulated by the mitochondrial protein mitofusin 2 (Mfn2), whose expression is activated in response to muscle injury. Mfn2 is required for growth and maturation of regenerating myofibers; in the absence of Mfn2, new myofibers arrested at a neonatal stage, characterized by centrally nucleated myofibers and loss of H3K27me3 repressive marks at the neonatal myosin heavy chain gene. A similar arrest at the neonatal stage was observed in infantile cases of human centronuclear myopathy. Mechanistically, Mfn2 upregulation suppressed expression of Hypoxia-induced Factor 1α (Hif1α), which is induced in the setting of muscle damage. Sustained Hif1α signaling blocked maturation of new myofibers at the neonatal-to-adult fate transition, revealing the existence of a checkpoint that delays muscle regeneration. Correspondingly, inhibition of Hif1α allowed myofibers to bypass the checkpoint, thereby accelerating the repair process. We conclude that skeletal muscle contains a regenerative checkpoint which regulates the speed of myofiber maturation in response to Mitofusin 2 and Hif1α activity.
    Keywords:  Epigenetics; Mitochondria; Muscle Biology; Stem cells
    DOI:  https://doi.org/10.1172/JCI161638
  11. Biofabrication. 2022 Sep 20.
    Multiscale engineered human skeletal muscles with perfusable vasculature and microvascular network recapitulating the fluid compartments.
    Hyeonyu Kim, Tatsuya Osaki, Roger D Kamm, Haruhiko Asada.
      Creating a vasculature in engineered human skeletal muscle tissues (ehSMTs) enables us to create thick tissues, increase cell survival in implantation, provide models of blood-organ barriers for drug testing, and enhance muscle differentiation through paracrine signaling. Here, contractile ehSMTs with a central perfusable vascular channel and microvascular networks growing from this central vasculature into the surrounding skeletal muscle tissue were newly demonstrated. Because coculturing muscle cells and endothelial cells requires incompatible media, we recapitulated the in vivo extracellular fluid compartments between blood plasma and interstitial fluid by creating an in vitro perfusable vasculature running through skeletal muscle tissue with a physiologic cell density. By using this model, we constructed large vascularized ehSMTs and showed the potential to be utilized for drug testing platforms. Also, we found that coculturing with two separate media from an early stage of muscle differentiation led to increased contractile force, thicker myotubes, and improved muscle differentiation.
    Keywords:  Angiogenesis; Engineered skeletal muscle tissues; Fluid compartments; Microenvironment; Myogenesis; Scalable tissue model; Vascularization
    DOI:  https://doi.org/10.1088/1758-5090/ac933d
  12. Antioxidants (Basel). 2022 Aug 29. pii: 1686. [Epub ahead of print]11(9):
    Inflammation: Roles in Skeletal Muscle Atrophy.
    Yanan Ji, Ming Li, Mengyuan Chang, Ruiqi Liu, Jiayi Qiu, Kexin Wang, Chunyan Deng, Yuntian Shen, Jianwei Zhu, Wei Wang, Lingchi Xu, Hualin Sun.
      Various diseases can cause skeletal muscle atrophy, usually accompanied by inflammation, mitochondrial dysfunction, apoptosis, decreased protein synthesis, and enhanced proteolysis. The underlying mechanism of inflammation in skeletal muscle atrophy is extremely complex and has not been fully elucidated, thus hindering the development of effective therapeutic drugs and preventive measures for skeletal muscle atrophy. In this review, we elaborate on protein degradation pathways, including the ubiquitin-proteasome system (UPS), the autophagy-lysosome pathway (ALP), the calpain and caspase pathways, the insulin growth factor 1/Akt protein synthesis pathway, myostatin, and muscle satellite cells, in the process of muscle atrophy. Under an inflammatory environment, various pro-inflammatory cytokines directly act on nuclear factor-κB, p38MAPK, and JAK/STAT pathways through the corresponding receptors, and then are involved in muscle atrophy. Inflammation can also indirectly trigger skeletal muscle atrophy by changing the metabolic state of other tissues or cells. This paper explores the changes in the hypothalamic-pituitary-adrenal axis and fat metabolism under inflammatory conditions as well as their effects on skeletal muscle. Moreover, this paper also reviews various signaling pathways related to muscle atrophy under inflammatory conditions, such as cachexia, sepsis, type 2 diabetes mellitus, obesity, chronic obstructive pulmonary disease, chronic kidney disease, and nerve injury. Finally, this paper summarizes anti-amyotrophic drugs and their therapeutic targets for inflammation in recent years. Overall, inflammation is a key factor causing skeletal muscle atrophy, and anti-inflammation might be an effective strategy for the treatment of skeletal muscle atrophy. Various inflammatory factors and their downstream pathways are considered promising targets for the treatment and prevention of skeletal muscle atrophy.
    Keywords:  ALP; UPS; inflammation; skeletal muscle atrophy
    DOI:  https://doi.org/10.3390/antiox11091686
  13. Med Sci Sports Exerc. 2022 Sep 22.
    Interrelated but not Time-aligned Response in Myogenic Regulatory Factors Demethylation and mRNA Expression after Divergent Exercise Bouts.
    Guilherme Defante Telles, Cleiton Augusto Libardi, Miguel Soares Conceição, Felipe Cassaro Vechin, Manoel Emílio Lixandrão, Flavia Regina Rotea Mangone, Ana Carolina Pavanelli, Maria Aparecida Nagai, Donny Michael Camera, John A Hawley, Carlos Ugrinowitsch.
      INTRODUCTION: DNA methylation regulates exercise-induced changes in the skeletal muscle transcriptome. However, the specificity and time-course responses in the myogenic regulatory factors DNA methylation and mRNA expression following divergent exercise modes is unknown.PURPOSE: To compare the time-course changes in DNA methylation and mRNA expression for selected myogenic regulatory factors (MYOD1, MYF5, and MYF6) immediately post-, 4 and 8 h following a single bout of resistance (RE), high-intensity interval (HIIE), and concurrent exercise (CE).
    METHODS: Nine healthy, but untrained males (age 23.9 ± 2.8y, body mass 70.1 ± 14.9 kg, peak oxygen uptake [VO2peak] 41.4 ± 5.2 ml·kg-1·min-1, mean ± SD) performed a counter-balanced, randomized order of RE (4x8-12 repetition maximum), HIIE (12x1 min sprints at VO2peak running velocity) and CE (RE followed by HIIE). Skeletal muscle biopsies (v. lateralis) were taken before (REST) immediately (0 h), 4 and 8 h after each exercise bout.
    RESULTS: Compared to REST, MYOD1, MYF5, and MYF6 mean methylation across all CpGs analysed was reduced after 4 and 8 h in response to all exercise protocols (P < 0.05). Reduced levels of MYOD1 methylation were observed after HIIE and CE compared to RE (P < 0.05). Compared to REST, all exercise bouts increased mRNA expression over time (MYOD1 at 4 and 8 h, and MYF6 at 4 h; P < 0.05). MYF5 mRNA expression was lower after 4 h compared to 0 h and higher at 8 h compared to 4 h (P < 0.05).
    CONCLUSIONS: We observed an interrelated but not time-aligned response between the exercise-induced changes in MRFs demethylation and mRNA expression following divergent exercise modes. Despite divergent contractile stimuli, changes in DNA methylation and mRNA expression in skeletal muscle were largely confined to the late (4-8 h) recovery period and similar between the different exercise challenges.
    DOI:  https://doi.org/10.1249/MSS.0000000000003049
  14. J Cachexia Sarcopenia Muscle. 2022 Sep 20.
    Ginsenoside Rd ameliorates muscle wasting by suppressing the signal transducer and activator of transcription 3 pathway.
    Yoseph Toni Wijaya, Tania Setiawan, Ita Novita Sari, Keunwan Park, Chan Hee Lee, Kae Won Cho, Yun Kyung Lee, Jae-Young Lim, Jeong Kyo Yoon, Sae Hwan Lee, Hyog Young Kwon.
      BACKGROUND: The effects of some drugs, aging, cancers, and other diseases can cause muscle wasting. Currently, there are no effective drugs for treating muscle wasting. In this study, the effects of ginsenoside Rd (GRd) on muscle wasting were studied.METHODS: Tumour necrosis factor-alpha (TNF-α)/interferon-gamma (IFN-γ)-induced myotube atrophy in mouse C2C12 and human skeletal myoblasts (HSkM) was evaluated based on cell thickness. Atrophy-related signalling, reactive oxygen species (ROS) level, mitochondrial membrane potential, and mitochondrial number were assessed. GRd (10 mg/kg body weight) was orally administered to aged mice (23-24 months old) and tumour-bearing (Lewis lung carcinoma [LLC1] or CT26) mice for 5 weeks and 16 days, respectively. Body weight, grip strength, inverted hanging time, and muscle weight were assessed. Histological analysis was also performed to assess the effects of GRd. The evolutionary chemical binding similarity (ECBS) approach, molecular docking, Biacore assay, and signal transducer and activator of transcription (STAT) 3 reporter assay were used to identify targets of GRd.
    RESULTS: GRd significantly induced hypertrophy in the C2C12 and HSkM myotubes (average diameter 50.8 ± 2.6% and 49.9% ± 3.7% higher at 100 nM, vs. control, P ≤ 0.001). GRd treatment ameliorated aging- and cancer-induced (LLC1 or CT26) muscle atrophy in mice, which was evidenced by significant increases in grip strength, hanging time, muscle mass, and muscle tissue cross-sectional area (1.3-fold to 4.6-fold, vs. vehicle, P ≤ 0.05; P ≤ 0.01; P ≤ 0.001). STAT3 was found to be a possible target of GRd by the ECBS approach and molecular docking assay. Validation of direct interaction between GRd and STAT3 was confirmed through Biacore analysis. GRd also inhibited STAT3 phosphorylation and STAT3 reporter activity, which led to the inhibition of STAT3 nuclear translocation and the suppression of downstream targets of STAT3, such as atrogin-1, muscle-specific RING finger protein (MuRF-1), and myostatin (MSTN) (29.0 ± 11.2% to 84.3 ± 30.5%, vs. vehicle, P ≤ 0.05; P ≤ 0.01; P ≤ 0.001). Additionally, GRd scavenged ROS (91.7 ± 1.4% reduction at 1 nM, vs. vehicle, P ≤ 0.001), inhibited TNF-α-induced dysregulation of ROS level, and improved mitochondrial integrity (P ≤ 0.05; P ≤ 0.01; P ≤ 0.001).
    CONCLUSIONS: GRd ameliorates aging- and cancer-induced muscle wasting. Our findings suggest that GRd may be a novel therapeutic agent or adjuvant for reversing muscle wasting.
    Keywords:  cachexia; ginsenoside Rd; muscle wasting; sarcopenia; signal transducer and activator of transcription 3
    DOI:  https://doi.org/10.1002/jcsm.13084
  15. Int J Mol Sci. 2022 Sep 14. pii: 10715. [Epub ahead of print]23(18):
    BAG3 Attenuates Ischemia-Induced Skeletal Muscle Necroptosis in Diabetic Experimental Peripheral Artery Disease.
    Arul M Mani, Karthik Dhanabalan, Victor Lamin, Thomas Wong, Madhu V Singh, Ayotunde O Dokun.
      Peripheral artery disease (PAD) is characterized by impaired blood flow to the lower extremities, resulting in ischemic limb injuries. Individuals with diabetes and PAD typically have more severe ischemic limb injuries and limb amputations, but the mechanisms involved are poorly understood. Previously, we identified BAG3 as a gene within a mouse genetic locus termed limb salvage QTL1 on mouse chromosome 7 that determined the extent of limb necrosis following ischemic injury in C57Bl/6 mice. Whether BAG3 deficiency plays a role in the severe ischemic injury observed in diabetic PAD is not known. In vitro, we found simulated ischemia enhanced BAG3 expression in primary human skeletal muscle cells, whereas BAG3 knockdown increased necroptosis markers and decreased cell viability. In vivo, ischemic skeletal muscles from hind limbs of high-fat diet (HFD)-fed mice showed poor BAG3 expression compared to normal chow diet (NCD)-fed mice, and this was associated with increased limb amputations. BAG3 overexpression in ischemic skeletal muscles from hind limbs of HFD mice rescued limb amputation and improved autophagy, necroptosis, skeletal muscle function and regeneration. Therefore, BAG3 deficiency in ischemic skeletal muscles contributes to the severity of ischemic limb injury in diabetic PAD, likely through autophagy and necroptosis pathways.
    Keywords:  BAG3; autophagy; diabetes; necroptosis; peripheral artery disease
    DOI:  https://doi.org/10.3390/ijms231810715
  16. BMC Genomics. 2022 Sep 17. 23(1): 657
    Transcriptomic profiles of muscular dystrophy with myositis (mdm) in extensor digitorum longus, psoas, and soleus muscles from mice.
    Pabodha Hettige, Uzma Tahir, Kiisa C Nishikawa, Matthew J Gage.
      BACKGROUND: Titinopathies are inherited muscular diseases triggered by genetic mutations in the titin gene. Muscular dystrophy with myositis (mdm) is one such disease caused by a LINE repeat insertion, leading to exon skipping and an 83-amino acid residue deletion in the N2A-PEVK region of mouse titin. This region has been implicated in a number of titin-titin ligand interactions, hence are important for myocyte signaling and health. Mice with this mdm mutation develop a severe and progressive muscle degeneration. The range of phenotypic differences observed in mdm mice shows that the deletion of this region induces a cascade of transcriptional changes extending to numerous signaling pathways affected by the titin filament. Previous research has focused on correlating phenotypic differences with muscle function in mdm mice. These studies have provided understanding of the downstream physiological effects resulting from the mdm mutation but only provide insights on processes that can be physiologically observed and measured. We used differential gene expression (DGE) to compare the transcriptomes of extensor digitorum longus (EDL), psoas and soleus muscles from wild-type and mdm mice to develop a deeper understand of these tissue-specific responses.RESULTS: The overall expression pattern observed shows a well-differentiated transcriptional signature in mdm muscles compared to wild type. Muscle-specific clusters observed within the mdm transcriptome highlight the level of variability of each muscle to the deletion. Differential gene expression and weighted gene co-expression network analysis showed a strong directional response in oxidative respiration-associated mitochondrial genes, which aligns with the poor shivering and non-shivering thermogenesis previously observed. Sln, which is a marker associated with shivering and non-shivering thermogenesis, showed the strongest expression change in fast-fibered muscles. No drastic changes in MYH expression levels were reported, which indicated an absence of major fiber-type switching events. Overall expression shifts in MYH isoforms, MARPs, and extracellular matrix associated genes demonstrated the transcriptional complexity associated with mdm mutation. The expression alterations in mitochondrial respiration and metabolism related genes in the mdm muscle dominated over other transcriptomic changes, and likely account for the late stage cellular responses in the mdm muscles.
    CONCLUSIONS: We were able to demonstrate that the complex nature of mdm mutation extends beyond a simple rearrangement in titin gene. EDL, psoas and soleus exemplify unique response modes observed in skeletal muscles with mdm mutation. Our data also raises the possibility that failure to maintain proper energy homeostasis in mdm muscles may contribute to the pathogenesis of the degenerative phenotype in mdm mice. Understanding the full disease-causing molecular cascade is difficult using bulk RNA sequencing techniques due to intricate nature of the disease. The development of the mdm phenotype is temporally and spatially regulated, hence future studies should focus on single fiber level investigations.
    Keywords:  Mdm; Mitochondria; RNA-Seq
    DOI:  https://doi.org/10.1186/s12864-022-08873-2
  17. Metabolites. 2022 Sep 11. pii: 855. [Epub ahead of print]12(9):
    Skeletal Muscle Mitochondrial and Perilipin Content in a Cohort of Obese Subjects Undergoing Moderate and High Intensity Training.
    Giuseppe Sirago, Filippo Vaccari, Stefano Lazzer, Andrea D'Amuri, Juana M Sanz, Marco V Narici, Carlo Reggiani, Angelina Passaro, Luana Toniolo.
      Obesity is a complex condition characterized by abnormal and excessive fat accumulation, resulting in an increased risk for severe health problems. Skeletal muscles play a major role in movement and fat catabolism, but the insulin resistance that comes with obesity makes it difficult to fulfill these tasks. In this study, we analyse two types of training protocols, moderate intensity continuous training (MICT) versus high intensity interval training (HIIT), in a cohort of obese subjects to establish which muscle adaptations favour fat consumption in response to exercise. Mitochondria play a role in fat oxidation. We found protein upregulation of mitochondrial biomarkers, TOMM20 and Cox-4, in HIIT but not in MICT, without detecting any shifts in fibre composition phenotype of the vastus lateralis in both training groups. Interestingly, both MICT and HIIT protocols showed increased protein levels of perilipin PLIN2, which is involved in the delivery and consumption of fats. HIIT also augmented perilipin PLIN5. Perilipins are involved in fat storage in skeletal muscles and their upregulation, along with the analysis of circulatory lipid profiles reported in the present study, suggest important adaptations induced by the two types of training protocols that favour fat consumption and weight loss in obese subjects.
    Keywords:  HIIT; MICT; human; mitochondria; obesity; perilipins; skeletal muscle
    DOI:  https://doi.org/10.3390/metabo12090855
  18. PLoS One. 2022 ;17(9): e0275175
    Muscle contractile exercise through a belt electrode device prevents myofiber atrophy, muscle contracture, and muscular pain in immobilized rat gastrocnemius muscle.
    Yuichiro Honda, Ayumi Takahashi, Natsumi Tanaka, Yasuhiro Kajiwara, Ryo Sasaki, Seima Okita, Junya Sakamoto, Minoru Okita.
      PURPOSE: Immobilization of skeletal muscles causes muscle atrophy, muscle contracture, and muscle pain, the mechanisms of which are related to macrophage accumulation. However, muscle contractile exercise through a belt electrode device may mitigate macrophage accumulation. We hypothesized that such exercise would be effective in preventing myofiber atrophy, muscle contracture, and muscular pain. This study tested this hypothesis in immobilized rat gastrocnemius muscle.MATERIALS AND METHODS: A total of 32 rats were divided into the following control and experimental groups: immobilization (immobilized treatment only), low-frequency (LF; immobilized treatment and muscle contractile exercise with a 2 s (do) /6 s (rest) duty cycle), and high-frequency (HF; immobilized treatment and muscle contractile exercise with a 2 s (do)/2 s (rest) duty cycle). Electrical stimulation was performed at 50 Hz and 4.7 mA, and muscle contractile exercise was applied to the lower limb muscles for 15 or 20 min/session (once daily) for 2 weeks (6 times/week). After the behavioral tests, the bilateral gastrocnemius muscles were collected for analysis.
    RESULTS: The number of macrophages, the Atrogin-1 and MuRF-1 mRNA expression, and the hydroxyproline content in the HF group were lower than those in the immobilization and LF groups. The cross-sectional area (CSA) of type IIb myofibers in the superficial region, the PGC-1α mRNA expression, and the range of motion of dorsiflexion in the HF group were significantly higher than those in the immobilization and LF groups. The pressure pain thresholds in the LF and HF groups were significantly higher than that in the immobilization group, and the nerve growth factor (NGF) content in the LF and HF groups was significantly lower than that in the immobilization group.
    CONCLUSION: Muscle contractile exercise through the belt electrode device may be effective in preventing immobilization-induced myofiber atrophy, muscle contracture, and muscular pain in the immobilized rat gastrocnemius muscle.
    DOI:  https://doi.org/10.1371/journal.pone.0275175
  19. Int J Mol Sci. 2022 Sep 16. pii: 10841. [Epub ahead of print]23(18):
    Myofibrillar Lattice Remodeling Is a Structural Cytoskeletal Predictor of Diaphragm Muscle Weakness in a Fibrotic mdx (mdx Cmah-/-) Model.
    Paul Ritter, Stefanie Nübler, Andreas Buttgereit, Lucas R Smith, Alexander Mühlberg, Julian Bauer, Mena Michael, Lucas Kreiß, Michael Haug, Elisabeth Barton, Oliver Friedrich.
      Duchenne muscular dystrophy (DMD) is a degenerative genetic myopathy characterized by complete absence of dystrophin. Although the mdx mouse lacks dystrophin, its phenotype is milder compared to DMD patients. The incorporation of a null mutation in the Cmah gene led to a more DMD-like phenotype (i.e., more fibrosis). Although fibrosis is thought to be the major determinant of 'structural weakness', intracellular remodeling of myofibrillar geometry was shown to be a major cellular determinant thereof. To dissect the respective contribution to muscle weakness, we assessed biomechanics and extra- and intracellular architecture of whole muscle and single fibers from extensor digitorum longus (EDL) and diaphragm. Despite increased collagen contents in both muscles, passive stiffness in mdx Cmah-/- diaphragm was similar to wt mice (EDL muscles were twice as stiff). Isometric twitch and tetanic stresses were 50% reduced in mdx Cmah-/- diaphragm (15% in EDL). Myofibrillar architecture was severely compromised in mdx Cmah-/- single fibers of both muscle types, but more pronounced in diaphragm. Our results show that the mdx Cmah-/- genotype reproduces DMD-like fibrosis but is not associated with changes in passive visco-elastic muscle stiffness. Furthermore, detriments in active isometric force are compatible with the pronounced myofibrillar disarray of the dystrophic background.
    Keywords:  cosine angle sum; multiphoton microscopy; muscular dystrophy; skeletal muscle; verniers density
    DOI:  https://doi.org/10.3390/ijms231810841
  20. J Gen Physiol. 2022 Nov 07. pii: e202213128. [Epub ahead of print]154(11):
    Nerve-dependent distribution of subsynaptic type 1 inositol 1,4,5-trisphosphate receptor at the neuromuscular junction.
    Pompeo Volpe, Alessandra Bosutti, Alessandra Nori, Riccardo Filadi, Gaia Gherardi, Gabor Trautmann, Sandra Furlan, Gabriele Massaria, Marina Sciancalepore, Aram Megighian, Paola Caccin, Annalisa Bernareggi, Michele Salanova, Roberta Sacchetto, Dorianna Sandonà, Paola Pizzo, Paola Lorenzon.
      Inositol 1,4,5-trisphosphate receptors (IP3Rs) are enriched at postsynaptic membrane compartments of the neuromuscular junction (NMJ), surrounding the subsynaptic nuclei and close to nicotinic acetylcholine receptors (nAChRs) of the motor endplate. At the endplate level, it has been proposed that nerve-dependent electrical activity might trigger IP3-associated, local Ca2+ signals not only involved in excitation-transcription (ET) coupling but also crucial to the development and stabilization of the NMJ itself. The present study was undertaken to examine whether denervation affects the subsynaptic IP3R distribution in skeletal muscles and which are the underlying mechanisms. Fluorescence microscopy, carried out on in vivo denervated muscles (following sciatectomy) and in vitro denervated skeletal muscle fibers from flexor digitorum brevis (FDB), indicates that denervation causes a reduction in the subsynaptic IP3R1-stained region, and such a decrease appears to be determined by the lack of muscle electrical activity, as judged by partial reversal upon field electrical stimulation of in vitro denervated skeletal muscle fibers.
    DOI:  https://doi.org/10.1085/jgp.202213128
  21. Sci Rep. 2022 Sep 23. 12(1): 15900
    Estrogen regulation of myokines that enhance osteoclast differentiation and activity.
    Andrew Norton, Kathleen Thieu, Cory W Baumann, Dawn A Lowe, Kim C Mansky.
      Osteoporosis and sarcopenia are maladies of aging that negatively affect more women than men. In recent years, it has become apparent that bone and muscle are coupled not only mechanically as muscle pulls on bone, but also at a higher level with myokines, biochemical and molecular signaling occurring between cells of the two tissues. However, how estrogen deficiency in females impacts the chemical crosstalk between bone and muscle cells is not understood. We hypothesize that changes in estrogen signaling alters myokine expression and intensifies bone loss in women. In our present study, we demonstrate that conditioned media from ovariectomized or skeletal muscle deficient in estrogen receptor α (ERα) expression enhances osteoclast differentiation and activity. Using a cytokine array, we identified myokines that have altered expressions in response to loss of estrogen signaling in muscle. Lastly, we demonstrate that conditional deletion of ERα in skeletal muscle results in osteopenia due to an increase in the osteoclast surface per bone surface. Our results suggest that estrogen signaling modulates expression of myokines that regulate osteoclast differentiation and activity.
    DOI:  https://doi.org/10.1038/s41598-022-19438-4
  22. Int J Mol Sci. 2022 Sep 13. pii: 10660. [Epub ahead of print]23(18):
    The Effect of Uridine on the State of Skeletal Muscles and the Functioning of Mitochondria in Duchenne Dystrophy.
    Mikhail V Dubinin, Vlada S Starinets, Natalia V Belosludtseva, Irina B Mikheeva, Yuliya A Chelyadnikova, Daria K Penkina, Alexander A Vedernikov, Konstantin N Belosludtsev.
      Duchenne muscular dystrophy is caused by the loss of functional dystrophin that secondarily causes systemic metabolic impairment in skeletal muscles and cardiomyocytes. The nutraceutical approach is considered as a possible complementary therapy for this pathology. In this work, we have studied the effect of pyrimidine nucleoside uridine (30 mg/kg/day for 28 days, i.p.), which plays an important role in cellular metabolism, on the development of DMD in the skeletal muscles of dystrophin deficient mdx mice, as well as its effect on the mitochondrial dysfunction that accompanies this pathology. We found that chronic uridine administration reduced fibrosis in the skeletal muscles of mdx mice, but it had no effect on the intensity of degeneration/regeneration cycles and inflammation, pseudohypetrophy, and muscle strength of the animals. Analysis of TEM micrographs showed that uridine also had no effect on the impaired mitochondrial ultrastructure of mdx mouse skeletal muscle. The administration of uridine was found to lead to an increase in the expression of the Drp1 and Parkin genes, which may indicate an increase in the intensity of organelle fission and the normalization of mitophagy. Uridine had little effect on OXPHOS dysfunction in mdx mouse mitochondria, and moreover, it was suppressed in the mitochondria of wild type animals. At the same time, uridine restored the transport of potassium ions and reduced the production of reactive oxygen species; however, this had no effect on the impaired calcium retention capacity of mdx mouse mitochondria. The obtained results demonstrate that the used dose of uridine only partially prevents mitochondrial dysfunction in skeletal muscles during Duchenne dystrophy, though it mitigates the development of destructive processes in skeletal muscles.
    Keywords:  Duchenne muscular dystrophy; lipid peroxidation; mitochondria; mitochondrial dysfunction; potassium transport; skeletal muscle; uridine
    DOI:  https://doi.org/10.3390/ijms231810660
  23. Physiol Rep. 2022 Sep;10(18): e15478
    Impaired fatigue resistance, sarcoplasmic reticulum function, and mitochondrial activity in soleus muscle of db/db mice.
    Hiro Yamamoto, Hiroaki Eshima, Saori Kakehi, Ryuzo Kawamori, Hirotaka Watada, Yoshifumi Tamura.
      Type 2 diabetes mellitus (T2DM) is characterized by reduced exercise tolerance due to increased fatigability in skeletal muscle. In this study, we investigated muscle fatigue resistance of soleus (SOL) muscle in obese type 2 diabetic model mice (db/db). No differences in muscle volume, absolute force, or specific force in SOL muscle were observed between db/db mice and control mice (db/+), while fatigue resistance evaluated by repeated tetanic contractions was significantly lower in db/db mice (30th tetani, db/+: 63.7 ± 4.7%, db/db: 51.3 ± 4.8%). The protein abundance related to Ca2+ release from the sarcoplasmic reticulum (SR) in SOL muscle was not different between db/db mice and db/+ mice, while SR Ca2+ -ATPase (Ca2+ reuptake to SR) protein was decreased in db/db mice compared to db/+ mice (db/+: 1.00 ± 0.17, db/db: 0.60 ± 0.04, relative units). In addition, mitochondrial oxidative enzyme activity (succinate dehydrogenase) was decreased in the SOL muscle of db/db mice (p < 0.05). These data suggest that fatigue resistance in slow-twitch dominant muscle is impaired in mice with T2DM. Decreased mitochondrial oxidative enzyme activity and impairment of Ca2+ uptake to SR, or both might be involved in the mechanisms.
    Keywords:  calcium; contractile function; diabetes; mitochondria; sarcoplasmic reticulum; skeletal muscle; slow twitch muscle
    DOI:  https://doi.org/10.14814/phy2.15478
  24. Front Biosci (Schol Ed). 2022 Jul 15. 14(3): 19
    Inducible Heat Shock Protein 70 Levels in Patients and the mdx Mouse Affirm Regulation during Skeletal Muscle Regeneration in Muscular Dystrophy.
    Gwenny Cosemans, Caroline Merckx, Jan L De Bleecker, Boel De Paepe.
      BACKGROUND: Stress-inducible heat shock protein 70 (HSP70) is both a protective chaperone involved in protein homeostasis and an immune regulator. In both capacities, HSP70 has been implicated in muscle disorders, yet with fragmented and differing results. In this study we aimed to compare results obtained in the mouse model for the severest form of muscular dystrophy (MD) equivalent to Duchenne MD, termed the mdx mouse, with results obtained in human MD.METHODS: Skeletal muscle and serum samples were obtained from 11 healthy controls, 11 fully characterized patients diagnosed with Becker MD and limb girdle MD (LGMD), and six muscle disease controls. In addition, muscle extracts were prepared from tibialis anterior of mdx and control mice at ages 4, 8 and 12 weeks. The HSP70 levels were quantified using RT-PCR, western blotting and protein arrays, and localized in muscle tissue sections using double immunofluorescence.
    RESULTS: We found selective and significant 2.2-fold upregulation of HSP70 protein in mdx tibialis muscle at the earliest disease phase only. In LGMD and Becker MD patients, HSP70 protein levels were not significantly different from those of healthy muscle and serum. HSP70 was localized to regenerating muscle fibers both in mouse and human MD skeletal muscle tissues. Toll-like receptor (TLR) 2 and TLR4 expression was moderately increased on the sarcolemma in MD muscle, yet protein levels were not significantly different from normal controls.
    CONCLUSIONS: HSP70 upregulation in MD appears disease stage-dependent, marking the phase of most active muscle regeneration in the mdx mouse. We postulate that well-timed supportive therapeutic interventions with HSP70 agonists could potentially improve muscle tissue's regenerative capacities in MD, attenuating loss of muscle mass while we await gene therapies to become more widely available.
    Keywords:  Becker muscular dystrophy; Duchenne muscular dystrophy; heat shock protein 70; limb girdle muscular dystrophy; muscle regeneration
    DOI:  https://doi.org/10.31083/j.fbs1403019
  25. Cells. 2022 Sep 13. pii: 2853. [Epub ahead of print]11(18):
    A Novel Muscle Atrophy Mechanism: Myocyte Degeneration Due to Intracellular Iron Deprivation.
    Dae Keun Suh, Won-Young Lee, Woo Jin Yeo, Bong Soo Kyung, Koo Whang Jung, Hye Kyung Seo, Yong-Soo Lee, Dong Won Suh.
      Muscle atrophy is defined as the progressive degeneration or shrinkage of myocytes and is triggered by factors such as aging, cancer, injury, inflammation, and immobilization. Considering the total amount of body iron stores and its crucial role in skeletal muscle, myocytes may have their own iron regulation mechanism. Although the detrimental effects of iron overload or iron deficiency on muscle function have been studied, the molecular mechanism of iron-dependent muscle atrophy has not been elucidated. Using human muscle tissues and in the mouse rotator cuff tear model, we confirmed an association between injury-induced iron depletion in myocytes and muscle atrophy. In differentiated C2C12 myotubes, the effects of iron deficiency on myocytes and the molecular mechanism of muscle atrophy by iron deficiency were evaluated. Our study revealed that the lower iron concentration in injured muscle was associated with the upregulation of ferroportin, an iron exporter that transports iron out of cells. Ferroportin expression was increased by hypoxia-inducible factor 1α (HIF1α), which is activated by muscle injury, and its expression is controlled by HIF1 inhibitor treatment. Iron deprivation caused myocyte loss and a marked depletion of mitochondrial membrane potential leading to muscle atrophy, together with increased levels of myostatin, the upstream regulator of atrogin1 and muscle RING-finger protein-1 (MuRF1). Myostatin expression under iron deficiency was mediated by an orphan nuclear receptor, dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome (DAX1).
    Keywords:  ferroportin; hypoxia-inducible factor 1; iron; muscle atrophy; myostatin; transcription factor
    DOI:  https://doi.org/10.3390/cells11182853
  26. Front Physiol. 2022 ;13 948985
    The impact of different exercise protocols on rat soleus muscle reinnervation and recovery following peripheral nerve lesion and regeneration.
    Michael Di Palma, Patrizia Ambrogini, Davide Lattanzi, Lorenza Brocca, Roberto Bottinelli, Riccardo Cuppini, Maria A Pellegrino, Stefano Sartini.
      Background: Incomplete functional recovery following traumatic peripheral nerve injury is common, mainly because not all axons successfully regenerate and reinnervate target muscles. Exercise can improve functional outcomes increasing the terminal sprouting during the muscle reinnervation. However, exercise is not a panacea per se. Indeed, the type of exercise adopted dramatically impacts the outcomes of rehabilitation therapy. To gain insight into the therapeutic effects of different exercise regimens on reinnervation following traumatic nerve lesion, we evaluated the impact of different clinically transferable exercise protocols (EPs) on metabolic and functional muscle recovery following nerve crush. Methods: The reinnervation of soleus muscle in adult nerve-crushed rats was studied following 6 days of different patterns (continuous or intermittent) and intensities (slow, mid, and fast) of treadmill running EPs. The effects of EPs on muscle fiber multiple innervation, contractile properties, metabolic adaptations, atrophy, and autophagy were assessed using functional and biochemical approaches. Results: Results showed that an intermittent mid-intensity treadmill EP improves soleus muscle reinnervation, whereas a slow continuous running EP worsens the functional outcome. However, the mid-intensity intermittent EP neither enhanced the critical mediators of exercise-induced metabolic adaptations, namely, PGC-1α, nor improved muscle atrophy. Conversely, the autophagy-related marker LC3 increased exclusively in the mid-intensity intermittent EP group. Conclusion: Our results demonstrated that an EP characterized by a mid-intensity intermittent activity enhances the functional muscle recovery upon a nerve crush, thus representing a promising clinically transferable exercise paradigm to improve recovery in humans following peripheral nerve injuries.
    Keywords:  autophagy; exercise; motor recovery; muscle reinnervation; peripheral nerve lesion; terminal axon sprouting
    DOI:  https://doi.org/10.3389/fphys.2022.948985
  27. Front Cell Dev Biol. 2022 ;10 934586
    Effects of mutant lamins on nucleo-cytoskeletal coupling in Drosophila models of LMNA muscular dystrophy.
    Nicholas M Shaw, Jose L Rios-Monterrosa, Gregory R Fedorchak, Margaret R Ketterer, Gary S Coombs, Jan Lammerding, Lori L Wallrath.
      The nuclei of multinucleated skeletal muscles experience substantial external force during development and muscle contraction. Protection from such forces is partly provided by lamins, intermediate filaments that form a scaffold lining the inner nuclear membrane. Lamins play a myriad of roles, including maintenance of nuclear shape and stability, mediation of nuclear mechanoresponses, and nucleo-cytoskeletal coupling. Herein, we investigate how disease-causing mutant lamins alter myonuclear properties in response to mechanical force. This was accomplished via a novel application of a micropipette harpooning assay applied to larval body wall muscles of Drosophila models of lamin-associated muscular dystrophy. The assay enables the measurement of both nuclear deformability and intracellular force transmission between the cytoskeleton and nuclear interior in intact muscle fibers. Our studies revealed that specific mutant lamins increase nuclear deformability while other mutant lamins cause nucleo-cytoskeletal coupling defects, which were associated with loss of microtubular nuclear caging. We found that microtubule caging of the nucleus depended on Msp300, a KASH domain protein that is a component of the linker of nucleoskeleton and cytoskeleton (LINC) complex. Taken together, these findings identified residues in lamins required for connecting the nucleus to the cytoskeleton and suggest that not all muscle disease-causing mutant lamins produce similar defects in subcellular mechanics.
    Keywords:  Drosophila; LINC complex; lamins; microtubules; muscle; muscular dystrophies; myonuclei
    DOI:  https://doi.org/10.3389/fcell.2022.934586
  28. Antioxidants (Basel). 2022 Aug 30. pii: 1706. [Epub ahead of print]11(9):
    Bile Acids Induce Alterations in Mitochondrial Function in Skeletal Muscle Fibers.
    Johanna Abrigo, Hugo Olguín, Danae Gutierrez, Franco Tacchi, Marco Arrese, Daniel Cabrera, Mayalen Valero-Breton, Alvaro A Elorza, Felipe Simon, Claudio Cabello-Verrugio.
      Cholestatic chronic liver disease is characterized by developing sarcopenia and elevated serum levels of bile acids. Sarcopenia is a skeletal muscle disorder with the hallmarks of muscle weakness, muscle mass loss, and muscle strength decline. Our previous report demonstrated that deoxycholic acid (DCA) and cholic acid (CA), through the membrane receptor TGR5, induce a sarcopenia-like phenotype in myotubes and muscle fibers. The present study aimed to evaluate the impact of DCA and CA on mitochondrial mass and function in muscle fibers and the role of the TGR5 receptor. To this end, muscle fibers obtained from wild-type and TGR5-/- mice were incubated with DCA and CA. Our results indicated that DCA and CA decreased mitochondrial mass, DNA, and potential in a TGR5-dependent fashion. Furthermore, with TGR5 participation, DCA and CA also reduced the oxygen consumption rate and complexes I and II from the mitochondrial electron transport chain. In addition, DCA and CA generated more mitochondrial reactive oxygen species than the control, which were abolished in TGR5-/- mice muscle fibers. Our results indicate that DCA and CA induce mitochondrial dysfunction in muscle fibers through a TGR5-dependent mechanism.
    Keywords:  TGR5 receptor; bile acids; mitochondria; muscle wasting; sarcopenia
    DOI:  https://doi.org/10.3390/antiox11091706
  29. Commun Biol. 2022 Sep 19. 5(1): 989
    Single nuclei transcriptomics of muscle reveals intra-muscular cell dynamics linked to dystrophin loss and rescue.
    Deirdre D Scripture-Adams, Kevin N Chesmore, Florian Barthélémy, Richard T Wang, Shirley Nieves-Rodriguez, Derek W Wang, Ekaterina I Mokhonova, Emilie D Douine, Jijun Wan, Isaiah Little, Laura N Rabichow, Stanley F Nelson, M Carrie Miceli.
      In Duchenne muscular dystrophy, dystrophin loss leads to chronic muscle damage, dysregulation of repair, fibro-fatty replacement, and weakness. We develop methodology to efficiently isolate individual nuclei from minute quantities of frozen skeletal muscle, allowing single nuclei sequencing of irreplaceable archival samples and from very small samples. We apply this method to identify cell and gene expression dynamics within human DMD and mdx mouse muscle, characterizing effects of dystrophin rescue by exon skipping therapy at single nuclei resolution. DMD exon 23 skipping events are directly observed and increased in myonuclei from treated mice. We describe partial rescue of type IIa and IIx myofibers, expansion of an MDSC-like myeloid population, recovery of repair/remodeling M2-macrophage, and repression of inflammatory POSTN1 + fibroblasts in response to exon skipping and partial dystrophin restoration. Use of this method enables exploration of cellular and transcriptomic mechanisms of dystrophin loss and repair within an intact muscle environment. Our initial findings will scaffold our future work to more directly examine muscular dystrophies and putative recovery pathways.
    DOI:  https://doi.org/10.1038/s42003-022-03938-0
  30. Cell Rep. 2022 Sep 20. pii: S2211-1247(22)01230-X. [Epub ahead of print]40(12): 111393
    SMN controls neuromuscular junction integrity through U7 snRNP.
    Sarah Tisdale, Meaghan Van Alstyne, Christian M Simon, George Z Mentis, Livio Pellizzoni.
      The neuromuscular junction (NMJ) is an essential synapse whose loss is a key hallmark of the neurodegenerative disease spinal muscular atrophy (SMA). Here, we show that activity of the SMA-determining SMN protein in the assembly of U7 small nuclear ribonucleoprotein (snRNP)-which functions in the 3'-end processing of replication-dependent histone mRNAs-is required for NMJ integrity. Co-expression of U7-specific Lsm10 and Lsm11 proteins selectively enhances U7 snRNP assembly, corrects histone mRNA processing defects, and rescues key structural and functional abnormalities of neuromuscular pathology in SMA mice-including NMJ denervation, decreased synaptic transmission, and skeletal muscle atrophy. Furthermore, U7 snRNP dysfunction drives selective loss of the synaptic organizing protein Agrin at NMJs innervating vulnerable muscles of SMA mice. These findings reveal a direct contribution of U7 snRNP dysfunction to neuromuscular pathology in SMA and suggest a role for histone gene regulation in maintaining functional synaptic connections between motor neurons and muscles.
    Keywords:  3′-end mRNA processing; CP: Neuroscience; Lsm proteins; RNP assembly; U7 small nuclear ribonucleoprotein (snRNP); histone gene regulation; motor neurons; neurodegeneration; neuromuscular junction (NMJ); spinal muscular atrophy (SMA); survival motor neuron (SMN)
    DOI:  https://doi.org/10.1016/j.celrep.2022.111393
  31. Front Physiol. 2022 ;13 989796
    Excitation-contraction coupling in mammalian skeletal muscle: Blending old and last-decade research.
    Pura Bolaños, Juan C Calderón.
      The excitation-contraction coupling (ECC) in skeletal muscle refers to the Ca2+-mediated link between the membrane excitation and the mechanical contraction. The initiation and propagation of an action potential through the membranous system of the sarcolemma and the tubular network lead to the activation of the Ca2+-release units (CRU): tightly coupled dihydropyridine and ryanodine (RyR) receptors. The RyR gating allows a rapid, massive, and highly regulated release of Ca2+ from the sarcoplasmic reticulum (SR). The release from triadic places generates a sarcomeric gradient of Ca2+ concentrations ([Ca2+]) depending on the distance of a subcellular region from the CRU. Upon release, the diffusing Ca2+ has multiple fates: binds to troponin C thus activating the contractile machinery, binds to classical sarcoplasmic Ca2+ buffers such as parvalbumin, adenosine triphosphate and, experimentally, fluorescent dyes, enters the mitochondria and the SR, or is recycled through the Na+/Ca2+ exchanger and store-operated Ca2+ entry (SOCE) mechanisms. To commemorate the 7th decade after being coined, we comprehensively and critically reviewed "old", historical landmarks and well-established concepts, and blended them with recent advances to have a complete, quantitative-focused landscape of the ECC. We discuss the: 1) elucidation of the CRU structures at near-atomic resolution and its implications for functional coupling; 2) reliable quantification of peak sarcoplasmic [Ca2+] using fast, low affinity Ca2+ dyes and the relative contributions of the Ca2+-binding mechanisms to the whole concert of Ca2+ fluxes inside the fibre; 3) articulation of this novel quantitative information with the unveiled structural details of the molecular machinery involved in mitochondrial Ca2+ handing to understand how and how much Ca2+ enters the mitochondria; 4) presence of the SOCE machinery and its different modes of activation, which awaits understanding of its magnitude and relevance in situ; 5) pharmacology of the ECC, and 6) emerging topics such as the use and potential applications of super-resolution and induced pluripotent stem cells (iPSC) in ECC. Blending the old with the new works better!
    Keywords:  Ca2+; Ca2+ channels; excitation-contraction coupling; fluorescence; mitochondria; ryanodine receptor—RYR1; skeletal muscle
    DOI:  https://doi.org/10.3389/fphys.2022.989796
  32. Commun Biol. 2022 Sep 19. 5(1): 987
    Stretching muscle cells induces transcriptional and splicing transitions and changes in SR proteins.
    Emma R Hinkle, R Eric Blue, Yi-Hsuan Tsai, Matthew Combs, Jacquelyn Davi, Alisha R Coffey, Aladin M Boriek, Joan M Taylor, Joel S Parker, Jimena Giudice.
      Alternative splicing is an RNA processing mechanism involved in skeletal muscle development and pathology. Muscular diseases exhibit splicing alterations and changes in mechanobiology leading us to investigate the interconnection between mechanical forces and RNA processing. We performed deep RNA-sequencing after stretching muscle cells. First, we uncovered transcriptional changes in genes encoding proteins involved in muscle function and transcription. Second, we observed that numerous mechanosensitive genes were part of the MAPK pathway which was activated in response to stretching. Third, we revealed that stretching skeletal muscle cells increased the proportion of alternatively spliced cassette exons and their inclusion. Fourth, we demonstrated that the serine and arginine-rich proteins exhibited stronger transcriptional changes than other RNA-binding proteins and that SRSF4 phosphorylation is mechanosensitive. Identifying SRSF4 as a mechanosensitive RNA-binding protein that might contribute to crosstalk between mechanotransduction, transcription, and splicing could potentially reveal novel insights into muscular diseases, particularly those with unknown etiologies.
    DOI:  https://doi.org/10.1038/s42003-022-03915-7
  33. Curr Osteoporos Rep. 2022 Sep 19.
    Role of the Gut Microbiome in Skeletal Muscle Physiology and Pathophysiology.
    Camille Lefevre, Laure B Bindels.
      PURPOSE OF REVIEW: This review aims to summarize the recent findings about the contribution of the gut microbiome to muscle pathophysiology and discuss molecular pathways that may be involved in such process. Related findings in the context of cancer cachexia are outlined.RECENT FINDINGS: Many bacterial metabolites have been reported to exert a beneficial or detrimental impact on muscle physiology. Most of the evidence concentrates on short-chain fatty acids (SCFAs), with an emerging role for bile acids, bacterial amino acid metabolites (bAAms), and bacterial polyphenol metabolites. Other molecular players worth considering include cytokines, hormones, lipopolysaccharides, and quorum sensing molecules. The current literature clearly establishes the ability for the gut microbiome to modulate muscle function and mass. The understanding of the mechanisms underlying this gut-muscle axis may lead to the delivery of novel therapeutic tools to tackle muscle wasting in cancer cachexia, chronic kidney disease, liver fibrosis, and age-related sarcopenia.
    Keywords:  Fibroblast growth factor 19; Indoxyl sulfate; Kynurenine; P-cresol sulfate; Takeda G protein–coupled receptor 5; Urolithin
    DOI:  https://doi.org/10.1007/s11914-022-00752-9
  34. J Physiol Biochem. 2022 Sep 20.
    Lipoxin A4 attenuated dexamethasone-induced muscle atrophy via activation of PGC-1α/Nrf2/TFAM pathway.
    Fatma H Rizk, Nema A Soliman, Shaimaa M Kashef, Amira A Elsaadany.
      Prolonged dexamethasone (DEX) administration causes skeletal muscle atrophy through induction of both oxidative stress and mitochondrial dysfunction. Lipoxin A4 (LXA4) is a recognized antioxidant but its effect against DEX-induced muscle atrophy has not been studied yet. This study aimed to assess the potential ameliorating effect of LXA4 on DEX-induced muscle atrophy and investigate the possible involvement of the mitochondrial dynamics pathway and the redox state in this effect. Forty male rats were divided into four groups; normal control, LXA4-treated, DEX-treated, and LXA4 plus DEX-treated. At the end of the experiment, LXA4 counteracted the effect of DEX on different parameters including muscle weight, muscle strength, serum creatine kinase activity, malondialdehyde and protein carbonyl contents, Na/K-ATPase and citrate synthase activities, mitochondrial transmembrane potential, mitochondrial transcription factor (TFAM), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and nuclear factor erythroid 2-related factor 2 (Nrf2). These findings signify the promising therapeutic effect of LXA4 against DEX-induced skeletal muscle atrophy and indicate the possible involvement of LXA4-induced mitochondrial activation in addition to its well-known antioxidant effects.
    Keywords:  Dexamethasone; Lipoxin A4; Mitochondrial function; Oxidative stress; Skeletal muscle atrophy
    DOI:  https://doi.org/10.1007/s13105-022-00925-1
  35. Sci Adv. 2022 Sep 23. 8(38): eabn4704
    Semirational bioengineering of AAV vectors with increased potency and specificity for systemic gene therapy of muscle disorders.
    Jihad El Andari, Edith Renaud-Gabardos, Warut Tulalamba, Jonas Weinmann, Louise Mangin, Quang Hong Pham, Susanne Hille, Antonette Bennett, Esther Attebi, Emanuele Bourges, Christian Leborgne, Nicolas Guerchet, Julia Fakhiri, Chiara Krämer, Ellen Wiedtke, Robert McKenna, Laurence Guianvarc'h, Magali Toueille, Giuseppe Ronzitti, Matthias Hebben, Federico Mingozzi, Thierry VandenDriessche, Mavis Agbandje-McKenna, Oliver J Müller, Marinee K Chuah, Ana Buj-Bello, Dirk Grimm.
      Bioengineering of viral vectors for therapeutic gene delivery is a pivotal strategy to reduce doses, facilitate manufacturing, and improve efficacy and patient safety. Here, we engineered myotropic adeno-associated viral (AAV) vectors via a semirational, combinatorial approach that merges AAV capsid and peptide library screens. We first identified shuffled AAVs with increased specificity in the murine skeletal muscle, diaphragm, and heart, concurrent with liver detargeting. Next, we boosted muscle specificity by displaying a myotropic peptide on the capsid surface. In a mouse model of X-linked myotubular myopathy, the best vectors-AAVMYO2 and AAVMYO3-prolonged survival, corrected growth, restored strength, and ameliorated muscle fiber size and centronucleation. In a mouse model of Duchenne muscular dystrophy, our lead capsid induced robust microdystrophin expression and improved muscle function. Our pipeline is compatible with complementary AAV genome bioengineering strategies, as demonstrated here with two promoters, and could benefit many clinical applications beyond muscle gene therapy.
    DOI:  https://doi.org/10.1126/sciadv.abn4704
  36. J Cell Physiol. 2022 Sep 20.
    FOXO1 is downregulated in obese mice subjected to short-term strength training.
    Rodrigo M Pereira, Kellen C da Cruz Rodrigues, Marcella R Sant'Ana, Alisson L da Rocha, Ana P Morelli, Allice S C Veras, Rodrigo S Gaspar, Célio J da Costa Fernandes, Giovana R Teixeira, Fernando M Simabuco, Adelino S R da Silva, Dennys E Cintra, Eduardo R Ropelle, José R Pauli, Leandro P de Moura.
      Obesity is a worldwide health problem and is directly associated with insulin resistance and type 2 diabetes. The liver is an important organ for the control of healthy glycemic levels, since insulin resistance in this organ reduces phosphorylation of forkhead box protein 1 (FOXO1) protein, leading to higher hepatic glucose production (HGP) and fasting hyperglycemia. Aerobic physical training is known as an important strategy in increasing the insulin action in the liver by increasing FOXO1 phosphorylation and reducing gluconeogenesis. However, little is known about the effects of strength training in this context. This study aimed to investigate the effects of short-term strength training on hepatic insulin sensitivity and glycogen synthase kinase-3β (GSK3β) and FOXO1 phosphorylation in obese (OB) mice. To achieve this goal, OB Swiss mice performed the strength training protocol (one daily session for 15 days). Short-term strength training increased the phosphorylation of protein kinase B and GSK3β in the liver after insulin stimulus and improved the control of HGP during the pyruvate tolerance test. On the other hand, sedentary OB animals reduced FOXO1 phosphorylation and increased the levels of nuclear FOXO1 in the liver, increasing the phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) content. The bioinformatics analysis also showed positive correlations between hepatic FOXO1 levels and gluconeogenic genes, reinforcing our findings. However, strength-trained animals reverted to this scenario, regardless of body adiposity changes. In conclusion, short-term strength training is an efficient strategy to enhance the insulin action in the liver of OB mice, contributing to glycemic control by reducing the activity of hepatic FOXO1 and lowering PEPCK and G6Pase contents.
    Keywords:  diabetes; gluconeogenesis; insulin sensitivity; liver; obesity; short-term strength training
    DOI:  https://doi.org/10.1002/jcp.30882
  37. Int J Mol Sci. 2022 Sep 08. pii: 10363. [Epub ahead of print]23(18):
    Gain-of-Function Dynamin-2 Mutations Linked to Centronuclear Myopathy Impair Ca2+-Induced Exocytosis in Human Myoblasts.
    Lucas Bayonés, María José Guerra-Fernández, Fernando Hinostroza, Ximena Báez-Matus, Jacqueline Vásquez-Navarrete, Luciana I Gallo, Sergio Parra, Agustín D Martínez, Arlek González-Jamett, Fernando D Marengo, Ana M Cárdenas.
      Gain-of-function mutations of dynamin-2, a mechano-GTPase that remodels membrane and actin filaments, cause centronuclear myopathy (CNM), a congenital disease that mainly affects skeletal muscle tissue. Among these mutations, the variants p.A618T and p.S619L lead to a gain of function and cause a severe neonatal phenotype. By using total internal reflection fluorescence microscopy (TIRFM) in immortalized human myoblasts expressing the pH-sensitive fluorescent protein (pHluorin) fused to the insulin-responsive aminopeptidase IRAP as a reporter of the GLUT4 vesicle trafficking, we measured single pHluorin signals to investigate how p.A618T and p.S619L mutations influence exocytosis. We show here that both dynamin-2 mutations significantly reduced the number and durations of pHluorin signals induced by 10 μM ionomycin, indicating that in addition to impairing exocytosis, they also affect the fusion pore dynamics. These mutations also disrupt the formation of actin filaments, a process that reportedly favors exocytosis. This altered exocytosis might importantly disturb the plasmalemma expression of functional proteins such as the glucose transporter GLUT4 in skeletal muscle cells, impacting the physiology of the skeletal muscle tissue and contributing to the CNM disease.
    Keywords:  GLUT4; IRAP; centronuclear myopathy; dynamin; dynamin-2 mutations; endocytosis; exocytosis; pHluorin
    DOI:  https://doi.org/10.3390/ijms231810363
  38. Cell Stress Chaperones. 2022 Sep 23.
    RNA binding motif protein 3 (RBM3) promotes protein kinase B (AKT) activation to enhance glucose metabolism and reduce apoptosis in skeletal muscle of mice under acute cold exposure.
    Yang Liu, Hongzhao Shi, Yajie Hu, Ruizhi Yao, Peng Liu, Yuying Yang, Shize Li.
      The main danger of cold stress to animals in cold regions is systemic metabolic changes and protein synthesis inhibition. RBM3, an exceptional cold shock protein, is rapidly upregulated in response to hypothermia to resist the adverse effects of cold stress. However, the mechanism of the protective effect and the rapid upregulation of RBM3 remains unclear. O-GlcNAcylation, an atypical O-glycosylation, is precisely regulated only by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) and participates in the signal transduction of multiple cellular stress responses as a "stress and nutrition receptor." Therefore, our study aimed to explore the mechanism of RBM3 regulating glucose metabolism and promoting survival in skeletal muscle under acute cold exposure. Meanwhile, our study verifies whether O-GlcNAcylation mediated by OGT rapidly upregulates RBM3. The blood and skeletal muscle of mice were collected at the end of cold exposure treatment for 0, 2, and 4 h. Changes in levels of RBM3, AKT, glycolysis apoptosis, and OGT were measured. The results show that acute cold exposure upregulated RBM3, OGT, and AKT phosphorylation and increased energy consumption, which enhanced glycolysis and prevent apoptosis. In the 32 °C mild hypothermia model in vitro, overexpression of RBM3 enhanced AKT phosphorylation. Meanwhile, inactivation of AKT by wortmannin resulted in increased apoptosis and decreased glucose metabolism in skeletal muscle under acute cold exposure. In addition, OGT-mediated O-GlcNAcylation of p65 was confirmed in mouse myoblast cell line (C2C12) cells at mild hypothermia. O-GlcNAcylation level affected p65 activity and nuclear translocation. Compared with wild type (WT) mice, RBM3 and p65 phosphorylation were decreased in specific skeletal muscle Ogt (KO) mice, whereas AKT phosphorylation, glycolysis, and apoptosis were increased. Taken together, O-GlcNAcylation of p65 upregulates RBM3 to promote AKT phosphorylation, enhance glucose metabolism, and reduce apoptosis in skeletal muscle of mice under acute cold exposure.
    Keywords:  AKT; Glucose metabolism; O-GlcNAc; RBM3; p65
    DOI:  https://doi.org/10.1007/s12192-022-01297-7
  39. Neurohospitalist. 2022 Oct;12(4): 597-606
    Skeletal Muscle Manifestations and Creatine Kinase in COVID-19.
    Sarah A Friedman, Zeinab Charmchi, Michael Silver, Nuri Jacoby, Jonathan Perk, Yaacov Anziska.
      Background and Purpose: Skeletal muscle symptoms and elevated creatine kinase (CK) levels have been consistently reported as part of the COVID-19 disease process. Previous studies have yet to show a consistent relationship between CK levels and skeletal muscle symptoms, disease severity, and death from COVID-19. The purpose of this study is to determine whether elevated CK is associated with a COVID-19 course requiring intubation, intensive care, and/or causing death. Secondary objectives: To determine if there is a relationship between elevated CK and (1) skeletal muscle symptoms/signs (2) complications of COVID-19 and (3) other diagnostic laboratory values.Methods: This is a retrospective, single center cohort study. Data were collected from March 13, 2020, to May 13, 2020. This study included 289 hospitalized patients with laboratory-confirmed SARS-CoV-2 and measured CK levels during admission.
    Results: Of 289 patients (mean age 68.5 [SD 13.8] years, 145 [50.2%] were men, 262 [90.7%] were African American) with COVID-19, 52 (18.0%) reported myalgia, 92 (31.8%) reported subjective weakness, and 132 (45.7%) had elevated CK levels (defined as greater than 220 U/L). Elevated CK was found to be associated with severity of disease, even when adjusting for inflammatory marker C-reactive protein (initial CK: OR 1.006 [95% CI: 1.002-1.011]; peak CK: OR 1.006 [95% CI: 1.002-1.01]; last CK: 1.009 [95% CI: 1.002-1.016]; q = .04). Creatine kinase was not found to be associated with skeletal muscle symptoms/signs or with other laboratory markers.
    Conclusions: Creatine kinase is of possible clinical significance and may be used as an additional data point in predicting the trajectory of the COVID-19 disease process.
    Keywords:  CK; COVID-19; Creatine Phosphokinase; SARS-CoV-2; coronavirus; creatine kinase; myalgia; myopathy
    DOI:  https://doi.org/10.1177/19418744221105961
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