bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2024–11–03
38 papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Lineage tracing of nuclei in skeletal myofibers uncovers distinct transcripts and interplay between myonuclear populations.
  2. Aging Skeletal Muscles: What Are the Mechanisms of Age-Related Loss of Strength and Muscle Mass, and Can We Impede Its Development and Progression?
  3. The 24-hour molecular landscape after exercise in humans reveals MYC is sufficient for muscle growth.
  4. Compound heterozygous RYR1-RM mouse model reveals disease pathomechanisms and muscle adaptations to promote postnatal survival.
  5. PERM1-An Emerging Transcriptional Regulator of Mitochondrial Biogenesis: A Systematic Review.
  6. Suppressing PDGFRβ Signaling Enhances Myocyte Fusion to Promote Skeletal Muscle Regeneration.
  7. Sucla2 Knock-Out in Skeletal Muscle Yields Mouse Model of Mitochondrial Myopathy With Muscle Type-Specific Phenotypes.
  8. Alternatively spliced MAP4 isoforms have key roles in maintaining microtubule organization and skeletal muscle function.
  9. PTPN1/2 inhibition promotes muscle stem cell differentiation in Duchenne muscular dystrophy.
  10. Muscle inflammation is regulated by NF-κB from multiple cells to control distinct states of wasting in cancer cachexia.
  11. Ageing leads to selective type II myofibre deterioration and denervation independent of reinnervative capacity in human skeletal muscle.
  12. Ror2 signaling regulated by differential Wnt proteins determines pathological fate of muscle mesenchymal progenitors.
  13. Mitochondrial-targeted plastoquinone therapy ameliorates early onset muscle weakness that precedes ovarian cancer cachexia in mice.
  14. Spiny mice are primed but fail to regenerate volumetric skeletal muscle loss injuries.
  15. A Deficiency in Glutamine-Fructose-6-Phosphate Transaminase 1 (Gfpt1) in Skeletal Muscle Results in Reduced Glycosylation of the Delta Subunit of the Nicotinic Acetylcholine Receptor (AChRδ).
  16. Skeletal muscle reprogramming enhances reinnervation after peripheral nerve injury.
  17. Myokines May Be the Answer to the Beneficial Immunomodulation of Tailored Exercise-A Narrative Review.
  18. Skeletal myotubes expressing ALS mutant SOD1 induce pathogenic changes, impair mitochondrial axonal transport, and trigger motoneuron death.
  19. Recent Advances of Exosomes Derived from Skeletal Muscle and Crosstalk with Other Tissues.
  20. Astragaloside IV Improves Muscle Atrophy by Modulating the Activity of UPS and ALP via Suppressing Oxidative Stress and Inflammation in Denervated Mice.
  21. An aged-related structural study of DHPR tetrads in peripheral couplings of human skeletal muscle.
  22. Cellular and transcriptomic changes by the supplementation of aged rat serum in human pluripotent stem cell-derived myogenic progenitors.
  23. Postsynaptic BMP signaling regulates myonuclear properties in Drosophila larval muscles.
  24. MBNL deficiency in motor neurons disrupts neuromuscular junction maintenance and gait coordination.
  25. Transcriptional Analysis of Cancer Cachexia: Conserved and Unique Features Across Pre-Clinical Models and Biological Sex.
  26. Abnormal expression of myosin heavy chains in early postnatal stages of spinal muscular atrophy type I at single fibre level.
  27. Ighmbp2 mutations and disease pathology: Defining differences that differentiate SMARD1 and CMT2S.
  28. The Gut Microbiota Involvement in the Panorama of Muscular Dystrophy Pathogenesis.
  29. Macrophages on the Run: exercise balances macrophage polarization for improved health.
  30. The Effect of Lower Limb Combined Neuromuscular Electrical Stimulation on Skeletal Muscle Cross-Sectional Area and Inflammatory Signaling.
  31. Skeletal muscle from TBC1D4 p.Arg684Ter variant carriers is severely insulin resistant but exhibits normal metabolic responses during exercise.
  32. Ionic medicine: exploiting metallic ions to stimulate skeletal muscle tissue regeneration.
  33. The Effect of Multi-Ingredient Protein versus Collagen Supplementation on Satellite Cell Properties in Males and Females.
  34. Short-term exercise counteracts accelerated ageing impacts on physical performance and liver health in mice.
  35. SAT1/ALOX15 Signaling Pathway Is Involved in Ferroptosis After Skeletal Muscle Contusion.
  36. Neuromuscular mechanisms for the fast decline in rate of force development with muscle disuse - a narrative review.
  37. Engineering Nanoclusters of Cell Adhesive Ligands on Biomaterial Surfaces: Superior Cell Proliferation and Myotube Formation for Skeletal Muscle Tissue Regeneration.
  38. Causal role of immune cells in muscle atrophy: mendelian randomization study.
  1. Nat Commun. 2024 Oct 30. 15(1): 9372
    Lineage tracing of nuclei in skeletal myofibers uncovers distinct transcripts and interplay between myonuclear populations.
    Chengyi Sun, Casey O Swoboda, Fabian Montecino Morales, Cristofer Calvo, Michael J Petrany, Sreeja Parameswaran, Andrew VonHandorf, Matthew T Weirauch, Christoph Lepper, Douglas P Millay.
      Multinucleated skeletal muscle cells need to acquire additional nuclei through fusion with activated skeletal muscle stem cells when responding to both developmental and adaptive growth stimuli. A fundamental question in skeletal muscle biology has been the reason underlying this need for new nuclei in cells that already harbor hundreds of nuclei. Here we utilize nuclear RNA-sequencing approaches and develop a lineage tracing strategy capable of defining the transcriptional state of recently fused nuclei and distinguishing this state from that of pre-existing nuclei. Our findings reveal the presence of conserved markers of newly fused nuclei both during development and after a hypertrophic stimulus in the adult. However, newly fused nuclei also exhibit divergent gene expression that is determined by the myogenic environment to which they fuse. Moreover, accrual of new nuclei through fusion is required for nuclei already resident in adult myofibers to mount a normal transcriptional response to a load-inducing stimulus. We propose a model of mutual regulation in the control of skeletal muscle development and adaptations, where newly fused and pre-existing myonuclear populations influence each other to maintain optimal functional growth.
    DOI:  https://doi.org/10.1038/s41467-024-53510-z
  2. Int J Mol Sci. 2024 Oct 11. pii: 10932. [Epub ahead of print]25(20):
    Aging Skeletal Muscles: What Are the Mechanisms of Age-Related Loss of Strength and Muscle Mass, and Can We Impede Its Development and Progression?
    Thomas Gustafsson, Brun Ulfhake.
      As we age, we lose muscle strength and power, a condition commonly referred to as sarcopenia (ICD-10-CM code (M62.84)). The prevalence of sarcopenia is about 5-10% of the elderly population, resulting in varying degrees of disability. In this review we emphasise that sarcopenia does not occur suddenly. It is an aging-induced deterioration that occurs over time and is only recognised as a disease when it manifests clinically in the 6th-7th decade of life. Evidence from animal studies, elite athletes and longitudinal population studies all confirms that the underlying process has been ongoing for decades once sarcopenia has manifested. We present hypotheses about the mechanism(s) underlying this process and their supporting evidence. We briefly review various proposals to impede sarcopenia, including cell therapy, reducing senescent cells and their secretome, utilising targets revealed by the skeletal muscle secretome, and muscle innervation. We conclude that although there are potential candidates and ongoing preclinical and clinical trials with drug treatments, the only evidence-based intervention today for humans is exercise. We present different exercise programmes and discuss to what extent the interindividual susceptibility to developing sarcopenia is due to our genetic predisposition or lifestyle factors.
    Keywords:  ageing; dynapenia; motor unit; muscle fibre atrophy; senescence
    DOI:  https://doi.org/10.3390/ijms252010932
  3. EMBO Rep. 2024 Oct 31.
    The 24-hour molecular landscape after exercise in humans reveals MYC is sufficient for muscle growth.
    Sebastian Edman, Ronald G Jones Iii, Paulo R Jannig, Rodrigo Fernandez-Gonzalo, Jessica Norrbom, Nicholas T Thomas, Sabin Khadgi, Pieter J Koopmans, Francielly Morena, Toby L Chambers, Calvin S Peterson, Logan N Scott, Nicholas P Greene, Vandre C Figueiredo, Christopher S Fry, Liu Zhengye, Johanna T Lanner, Yuan Wen, Björn Alkner, Kevin A Murach, Ferdinand von Walden.
      A detailed understanding of molecular responses to a hypertrophic stimulus in skeletal muscle leads to therapeutic advances aimed at promoting muscle mass. To decode the molecular factors regulating skeletal muscle mass, we utilized a 24-h time course of human muscle biopsies after a bout of resistance exercise. Our findings indicate: (1) the DNA methylome response at 30 min corresponds to upregulated genes at 3 h, (2) a burst of translation- and transcription-initiation factor-coding transcripts occurs between 3 and 8 h, (3) changes to global protein-coding gene expression peaks at 8 h, (4) ribosome-related genes dominate the mRNA landscape between 8 and 24 h, (5) methylation-regulated MYC is a highly influential transcription factor throughout recovery. To test whether MYC is sufficient for hypertrophy, we periodically pulse MYC in skeletal muscle over 4 weeks. Transient MYC increases muscle mass and fiber size in the soleus of adult mice. We present a temporally resolved resource for understanding molecular adaptations to resistance exercise in muscle ( http://data.myoanalytics.com ) and suggest that controlled MYC doses influence the exercise-related hypertrophic transcriptional landscape.
    Keywords:  Biopsy; Methylome; Time Course; Transcription Factors; Transcriptome
    DOI:  https://doi.org/10.1038/s44319-024-00299-z
  4. FASEB J. 2024 Oct;38(20): e70120
    Compound heterozygous RYR1-RM mouse model reveals disease pathomechanisms and muscle adaptations to promote postnatal survival.
    Chen Liang, Sundeep Malik, Miao He, Linda Groom, Sara K Ture, Thomas N O'Connor, Craig N Morrell, Robert T Dirksen.
      Pathogenic variants in the type I ryanodine receptor (RYR1) result in a wide range of muscle disorders referred to as RYR1-related myopathies (RYR1-RM). We developed the first RYR1-RM mouse model resulting from co-inheritance of two different RYR1 missense alleles (Ryr1TM/SC-ΔL mice). Ryr1TM/SC-ΔL mice exhibit a severe, early onset myopathy characterized by decreased body/muscle mass, muscle weakness, hypotrophy, reduced RYR1 expression, and unexpectedly, incomplete postnatal lethality with a plateau survival of ~50% at 12 weeks of age. Ryr1TM/SC-ΔL mice display reduced respiratory function, locomotor activity, and in vivo muscle strength. Extensor digitorum longus muscles from Ryr1TM/SC-ΔL mice exhibit decreased cross-sectional area of type IIb and type IIx fibers, as well as a reduction in number of type IIb fibers. Ex vivo functional analyses revealed reduced Ca2+ release and specific force production during electrically-evoked twitch stimulation. In spite of a ~threefold reduction in RYR1 expression in single muscle fibers from Ryr1TM/SC-ΔL mice at 4 weeks and 12 weeks of age, RYR1 Ca2+ leak was not different from that of fibers from control mice at either age. Proteomic analyses revealed alterations in protein synthesis, folding, and degradation pathways in the muscle of 4- and 12-week-old Ryr1TM/SC-ΔL mice, while proteins involved in the extracellular matrix, dystrophin-associated glycoprotein complex, and fatty acid metabolism were upregulated in Ryr1TM/SC-ΔL mice that survive to 12 weeks of age. These findings suggest that adaptations that optimize RYR1 expression/Ca2+ leak balance, sarcolemmal stability, and fatty acid biosynthesis provide Ryr1TM/SC-ΔL mice with an increased survival advantage during postnatal development.
    Keywords:  calcium signaling; congenital myopathy; excitation‐contraction coupling; proteomics; ryanodine receptor; skeletal muscle
    DOI:  https://doi.org/10.1096/fj.202401189R
  5. Genes (Basel). 2024 Oct 09. pii: 1305. [Epub ahead of print]15(10):
    PERM1-An Emerging Transcriptional Regulator of Mitochondrial Biogenesis: A Systematic Review.
    Eveline Soares Menezes, Zeyu Wu, John R M Renwick, Andres Moran-MacDonald, Brendon J Gurd.
       BACKGROUND/OBJECTIVES: This systematic review aims to explore the role of PERM1 across different organisms, tissues, and cellular functions, with a particular focus on its involvement in regulating skeletal muscle mitochondrial biogenesis.
    METHODS: This systematic review follows The PRISMA 2020 Statement. We used the Covidence systematic review software for abstract/title screening, full-text review, and data extraction. The review included studies that examined PERM1 expression or activity in skeletal muscle, heart, and adipose tissue and/or cells, from mice, rats, and humans, and involved exercise or disease models. Risk of bias was assessed using the Cochrane Collaboration tool, and the data were extracted and synthesized qualitatively, with bioinformatic analyses performed using the MetaMEx database.
    RESULTS: Twenty-one studies were included in our data extraction process, where 10 studies involved humans, 21 involved mice, four involved rats, and 11 involved cells.
    CONCLUSIONS: PERM1 in skeletal muscle increases with endurance exercise, affecting muscle function and oxidative metabolism, but its role in humans is not well understood. In cardiac tissue, PERM1 is vital for function and mitochondrial biogenesis purposes, but decreases with disease and pressure overload. Our review synthesizes the current understanding of PERM1's function, raises awareness of its role in mitochondrial regulation, and identifies key areas for future research in the field.
    Keywords:  cardiac function; disease models; endurance exercise; oxidative metabolism; skeletal muscle adaptation; therapeutic target
    DOI:  https://doi.org/10.3390/genes15101305
  6. bioRxiv. 2024 Oct 18. pii: 2024.10.15.618247. [Epub ahead of print]
    Suppressing PDGFRβ Signaling Enhances Myocyte Fusion to Promote Skeletal Muscle Regeneration.
    Siwen Xue, Abigail M Benvie, Jamie E Blum, Nikolai J Kolba, Benjamin D Cosgrove, Anna Thalacker-Mercer, Daniel C Berry.
      Muscle cell fusion is critical for forming and maintaining multinucleated myotubes during skeletal muscle development and regeneration. However, the molecular mechanisms directing cell-cell fusion are not fully understood. Here, we identify platelet-derived growth factor receptor beta (PDGFRβ) signaling as a key modulator of myocyte fusion in adult muscle cells. Our findings demonstrate that genetic deletion of Pdgfrβ enhances muscle regeneration and increases myofiber size, whereas PDGFRβ activation impairs muscle repair. Inhibition of PDGFRβ activity promotes myonuclear accretion in both mouse and human myotubes, whereas PDGFRβ activation stalls myotube development by preventing cell spreading to limit fusion potential. Transcriptomics analysis show that PDGFRβ signaling cooperates with TGFβ signaling to direct myocyte size and fusion. Mechanistically, PDGFRβ signaling requires STAT1 activation, and blocking STAT1 phosphorylation enhances myofiber repair and size during regeneration. Collectively, PDGFRβ signaling acts as a regenerative checkpoint and represents a potential clinical target to rapidly boost skeletal muscle repair.
    DOI:  https://doi.org/10.1101/2024.10.15.618247
  7. J Cachexia Sarcopenia Muscle. 2024 Oct 31.
    Sucla2 Knock-Out in Skeletal Muscle Yields Mouse Model of Mitochondrial Myopathy With Muscle Type-Specific Phenotypes.
    Makayla S Lancaster, Paul Hafen, Andrew S Law, Catalina Matias, Timothy Meyer, Kathryn Fischer, Marcus Miller, Chunhai Hao, Patrick Gillespie, David McKinzie, Jeffrey J Brault, Brett H Graham.
       BACKGROUND: Pathogenic variants in subunits of succinyl-CoA synthetase (SCS) are associated with mitochondrial encephalomyopathy in humans. SCS catalyses the conversion of succinyl-CoA to succinate coupled with substrate-level phosphorylation of either ADP or GDP in the TCA cycle. This report presents a muscle-specific conditional knock-out (KO) mouse model of Sucla2, the ADP-specific beta subunit of SCS, generating a novel in vivo model of mitochondrial myopathy.
    METHODS: The mouse model was generated using the Cre-Lox system, with the human skeletal actin (HSA) promoter driving Cre-recombination of a CRISPR-Cas9-generated Sucla2 floxed allele within skeletal muscle. Inactivation of Sucla2 was validated using RT-qPCR and western blot, and both enzyme activity and serum metabolites were quantified by mass spectrometry. To characterize the model in vivo, whole-body phenotyping was conducted, with mice undergoing a panel of strength and locomotor behavioural assays. Additionally, ex vivo contractility experiments were performed on the soleus (SOL) and extensor digitorum longus (EDL) muscles. SOL and EDL cryosections were also subject to imaging analyses to assess muscle fibre-specific phenotypes.
    RESULTS: Molecular validation confirmed 68% reduction of Sucla2 transcript within the mutant skeletal muscle (p < 0.001) and 95% functionally reduced SUCLA2 protein (p < 0.0001). By 3 weeks of age, Sucla2 KO mice were 44% the size of controls by body weight (p < 0.0001). Mutant mice also exhibited 34%-40% reduced grip strength (p < 0.01) and reduced spontaneous exercise, spending about 88% less cumulative time on a running wheel (p < 0.0001). Contractile function was also perturbed in a muscle-specific manner; although no genotype-specific deficiencies were seen in EDL function, SUCLA2-deficient SOL muscles generated 40% less specific tetanic force (p < 0.0001), alongside slower contraction and relaxation rates (p < 0.001). Similarly, a SOL-specific threefold increase in mitochondria (p < 0.0001) was observed, with qualitatively increased staining for both COX and SDH, and the proportion of Type 1 myosin heavy chain expressing fibres within the SOL was nearly doubled (95% increase, p < 0.0001) in the Sucla2 KO mice compared with that in controls.
    CONCLUSIONS: SUCLA2 loss within murine skeletal muscle yields a model of SCS-deficient mitochondrial myopathy with reduced body weight, muscle weakness and exercise intolerance. Physiological and morphological analyses of hindlimb muscles showed remarkable differences in ex vivo function and cellular consequences between the EDL and SOL muscles, with SOL muscles significantly more impacted by Sucla2 inactivation. This novel model will provide an invaluable tool for investigations of muscle-specific and fibre type-specific pathogenic mechanisms to better understand SCS-deficient myopathy.
    Keywords:  contractility; extensor digitorum longus; fibre‐type switching; mitochondrial myopathy; soleus; succinyl‐CoA synthetase
    DOI:  https://doi.org/10.1002/jcsm.13617
  8. iScience. 2024 Nov 15. 27(11): 111104
    Alternatively spliced MAP4 isoforms have key roles in maintaining microtubule organization and skeletal muscle function.
    Lathan Lucas, Larissa Nitschke, Brandon Nguyen, James A Loehr, George G Rodney, Thomas A Cooper.
      Skeletal muscle cells (myofibers) are elongated non-mitotic, multinucleated syncytia that have adapted a microtubule lattice. Microtubule-associated proteins (MAPs) play roles in regulating microtubule architecture. The most abundant MAP in skeletal muscle is MAP4. MAP4 consists of a ubiquitous MAP4 isoform (uMAP4), expressed in most tissues, and a striated-muscle-specific alternatively spliced isoform (mMAP4) that includes a 3,180-nucleotide exon (exon 8). To determine the role of mMAP4 in skeletal muscle, we generated mice that lack mMAP4 and express only uMAP4 due to genomic deletion of exon 8. We demonstrate that loss of mMAP4 leads to disorganized microtubule architecture and intrinsic loss of force generation. We show that mMAP4 exhibits enhanced association with microtubules compared to uMAP4 and that both the loss of mMAP4 and the concomitant gain of uMAP4 cause loss of muscle function. These results demonstrate the critical role for balanced expression of mMAP4 and uMAP4 for skeletal muscle homeostasis.
    Keywords:  Cellular physiology; Functional aspects of cell biology; Molecular Structure; Molecular physiology
    DOI:  https://doi.org/10.1016/j.isci.2024.111104
  9. Life Sci Alliance. 2025 Jan;pii: e202402831. [Epub ahead of print]8(1):
    PTPN1/2 inhibition promotes muscle stem cell differentiation in Duchenne muscular dystrophy.
    Yiyang Liu, Shulei Li, Rebecca Robertson, Jules A Granet, Isabelle Aubry, Romina L Filippelli, Michel L Tremblay, Natasha C Chang.
      Duchenne muscular dystrophy (DMD) is a lethal disease caused by mutations in the DMD gene that encodes dystrophin. Dystrophin deficiency also impacts muscle stem cells (MuSCs), resulting in impaired asymmetric stem cell division and myogenic commitment. Using MuSCs from DMD patients and the DMD mouse model mdx, we found that PTPN1 phosphatase expression is up-regulated and STAT3 phosphorylation is concomitantly down-regulated in DMD MuSCs. To restore STAT3-mediated myogenic signaling, we examined the effect of K884, a novel PTPN1/2 inhibitor, on DMD MuSCs. Treatment with K884 enhanced STAT3 phosphorylation and promoted myogenic differentiation of DMD patient-derived MuSCs. In MuSCs from mdx mice, K884 treatment increased the number of asymmetric cell divisions, correlating with enhanced myogenic differentiation. Interestingly, the pro-myogenic effect of K884 is specific to human and murine DMD MuSCs and is absent from control MuSCs. Moreover, PTPN1/2 loss-of-function experiments indicate that the pro-myogenic impact of K884 is mediated mainly through PTPN1. We propose that PTPN1/2 inhibition may serve as a therapeutic strategy to restore the myogenic function of MuSCs in DMD.
    DOI:  https://doi.org/10.26508/lsa.202402831
  10. Cell Rep. 2024 Oct 29. pii: S2211-1247(24)01276-2. [Epub ahead of print]43(11): 114925
    Muscle inflammation is regulated by NF-κB from multiple cells to control distinct states of wasting in cancer cachexia.
    Benjamin R Pryce, Alexander Oles, Erin E Talbert, Martin J Romeo, Silvia Vaena, Sudarshana Sharma, Victoria Spadafora, Lauren Tolliver, David A Mahvi, Katherine A Morgan, William P Lancaster, Eryn Beal, Natlie Koren, Bailey Watts, Morgan Overstreet, Stefano Berto, Suganya Subramanian, Kubra Calisir, Anna Crawford, Brian Neelon, Michael C Ostrowski, Teresa A Zimmers, James G Tidball, David J Wang, Denis C Guttridge.
      Although cancer cachexia is classically characterized as a systemic inflammatory disorder, emerging evidence indicates that weight loss also associates with local tissue inflammation. We queried the regulation of this inflammation and its causality to cachexia by exploring skeletal muscle, whose atrophy strongly associates with poor outcomes. Using multiple mouse models and patient samples, we show that cachectic muscle is marked by enhanced innate immunity. Nuclear factor κB (NF-κB) activity in multiple cells, including satellite cells, myofibers, and fibro-adipogenic progenitors, promotes macrophage expansion equally derived from infiltrating monocytes and resident cells. Moreover, NF-κB-activated cells and macrophages undergo crosstalk; NF-κB+ cells recruit macrophages to inhibit regeneration and promote atrophy but, interestingly, also protect myofibers, while macrophages stimulate NF-κB+ cells to sustain an inflammatory feedforward loop. Together, we propose that NF-κB functions in multiple cells in the muscle microenvironment to stimulate macrophages that both promote and protect against muscle wasting in cancer.
    Keywords:  CP: Cancer; CP: Immunology; NF-κB; cancer cachexia; fibro-adipogenic progenitors; macrophages; muscle progenitor cells; pancreatic cancer
    DOI:  https://doi.org/10.1016/j.celrep.2024.114925
  11. Exp Physiol. 2024 Oct 28.
    Ageing leads to selective type II myofibre deterioration and denervation independent of reinnervative capacity in human skeletal muscle.
    Oscar Horwath, Marcus Moberg, Sebastian Edman, Andrew Philp, William Apró.
      Age-related loss of muscle mass and function is underpinned by changes at the myocellular level. However, our understanding of the aged muscle phenotype might be confounded by factors secondary to ageing per se, such as inactivity and adiposity. Here, using healthy, lean, recreationally active, older men, we investigated the impact of ageing on myocellular properties in skeletal muscle. Muscle biopsies were obtained from young men (22 ± 3 years, n = 10) and older men (69 ± 3 years, n = 11) matched for health status, activity level and body mass index. Immunofluorescence was used to assess myofibre composition, morphology (size and shape), capillarization, the content of satellite cells and myonuclei, the spatial relationship between satellite cells and capillaries, denervation and myofibre grouping. Compared with young muscle, aged muscle contained 53% more type I myofibres, in addition to smaller (-32%) and misshapen (3%) type II myofibres (P < 0.05). Aged muscle manifested fewer capillaries (-29%) and satellite cells (-38%) surrounding type II myofibres (P < 0.05); however, the spatial relationship between these two remained intact. The proportion of denervated myofibres was ∼2.6-fold higher in old than young muscle (P < 0.05). Aged muscle had more grouped type I myofibres (∼18-fold), primarily driven by increased size of existing groups rather than increased group frequency (P < 0.05). Aged muscle displayed selective deterioration of type II myofibres alongside increased denervation and myofibre grouping. These data are key to understanding the cellular basis of age-related muscle decline and reveal a pressing need to fine-tune strategies to preserve type II myofibres and innervation status in ageing populations.
    Keywords:  NCAM; Pax7; ageing; human skeletal muscle; sarcopenia
    DOI:  https://doi.org/10.1113/EP092222
  12. Cell Death Dis. 2024 Oct 29. 15(10): 784
    Ror2 signaling regulated by differential Wnt proteins determines pathological fate of muscle mesenchymal progenitors.
    Koki Kamizaki, Mitsuko Katsukawa, Ayano Yamamoto, So-Ichiro Fukada, Akiyoshi Uezumi, Mitsuharu Endo, Yasuhiro Minami.
      Skeletal muscle mesenchymal progenitors (MPs) play a critical role in supporting muscle regeneration. However, under pathological conditions, they contribute to intramuscular adipose tissue accumulation, involved in muscle diseases, including muscular dystrophy and sarcopenia, age-related muscular atrophy. How MP fate is determined in these different contexts remains unelucidated. Here, we report that Ror2, a non-canonical Wnt signaling receptor, is selectively expressed in MPs and regulates their pathological features in a differential ligand-dependent manner. We identified Wnt11 and Wnt5b as ligands of Ror2. In vitro, Wnt11 inhibited MP senescence, which is required for normal muscle regeneration, and Wnt5b promoted MP proliferation. We further found that both Wnts are abundant in degenerating muscle and synergistically stimulate Ror2, leading to unwanted MP proliferation and eventually intramuscular adipose tissue accumulation. These findings provide evidence that Ror2-mediated signaling elicited by differential Wnts plays a critical role in determining the pathological fate of MPs.
    DOI:  https://doi.org/10.1038/s41419-024-07173-9
  13. bioRxiv. 2024 Oct 25. pii: 2024.10.22.619751. [Epub ahead of print]
    Mitochondrial-targeted plastoquinone therapy ameliorates early onset muscle weakness that precedes ovarian cancer cachexia in mice.
    Luca J Delfinis, Shahrzad Khajehzadehshoushtar, Luke D Flewwelling, Nathaniel J Andrews, Madison C Garibotti, Shivam Gandhi, Aditya N Brahmbhatt, Brooke A Morris, Bianca Garlisi, Sylvia Lauks, Caroline Aitken, Stavroula Tsitkanou, Jeremy A Simpson, Nicholas P Greene, Arthur J Cheng, Jim Petrik, Christopher G R Perry.
      Cancer cachexia, and the related loss of muscle and strength, worsens quality of life and lowers overall survival. Recently, a novel 'pre-atrophy' muscle weakness was identified during early-stage cancer. While mitochondrial stress responses are associated with early-stage pre-atrophy weakness, a causal relationship has not been established. Using a robust mouse model of metastatic epithelial ovarian cancer (EOC)-induced cachexia, we found the well-established mitochondrial-targeted plastoquinone SkQ1 partially prevents pre-atrophy weakness in the diaphragm. Furthermore, SkQ1 improved force production during atrophy without preventing atrophy itself in the tibialis anterior and diaphragm. EOC reduced flexor digitorum brevis (FDB) force production and myoplasmic free calcium ([Ca 2+ ] i ) during contraction in single muscle fibers, both of which were prevented by SkQ1. Remarkably, changes in mitochondrial reactive oxygen species and pyruvate metabolism were heterogeneous across time and between muscle types which highlights a considerable complexity in the relationships between mitochondria and muscle remodeling throughout EOC. These discoveries identify that muscle weakness can occur independent of atrophy throughout EOC in a manner that is linked to improved calcium handling. The findings also demonstrate that mitochondrial-targeted therapies exert a robust effect in preserving muscle force during the early pre-atrophy period and in late-stage EOC once cachexia has become severe.
    DOI:  https://doi.org/10.1101/2024.10.22.619751
  14. Skelet Muscle. 2024 Oct 29. 14(1): 26
    Spiny mice are primed but fail to regenerate volumetric skeletal muscle loss injuries.
    Mackenzie L Davenport, Amaya Fong, Kaela N Albury, C Spencer Henley-Beasley, Elisabeth R Barton, Malcolm Maden, Maurice S Swanson.
       BACKGROUND: In recent years, the African spiny mouse Acomys cahirinus has been shown to regenerate a remarkable array of severe internal and external injuries in the absence of a fibrotic response, including the ability to regenerate full-thickness skin excisions, ear punches, severe kidney injuries, and complete transection of the spinal cord. While skeletal muscle is highly regenerative in adult mammals, Acomys displays superior muscle regeneration properties compared with standard laboratory mice following several injuries, including serial cardiotoxin injections of skeletal muscle and volumetric muscle loss (VML) of the panniculus carnosus muscle following full-thickness excision injuries. VML is an extreme muscle injury defined as the irrecoverable ablation of muscle mass, most commonly resulting from combat injuries or surgical debridement. Barriers to the treatment of VML injury include early and prolonged inflammatory responses that promote fibrotic repair and the loss of structural and mechanical cues that promote muscle regeneration. While the regeneration of the panniculus carnosus in Acomys is impressive, its direct relevance to the study of VML in patients is less clear as this muscle has largely been lost in humans, and, while striated, is not a true skeletal muscle. We therefore sought to test the ability of Acomys to regenerate a skeletal muscle more commonly used in VML injury models.
    METHODS: We performed two different VML injuries of the Acomys tibialis anterior muscle and compared the regenerative response to a standard laboratory mouse strain, Mus C57BL6/J.
    RESULTS: Neither Acomys nor Mus recovered lost muscle mass or myofiber number within three months following VML injury, and Acomys also failed to recover force production better than Mus. In contrast, Acomys continued to express eMHC within the injured area even three months following injury, whereas Mus ceased expressing eMHC less than one-month post-injury, suggesting that Acomys muscle was primed, but failed, to regenerate.
    CONCLUSIONS: While the panniculus carnosus muscle in Acomys regenerates following VML injury in the context of full-thickness skin excision, this regenerative ability does not translate to regenerative repair of a skeletal muscle.
    Keywords:   Acomys ; Muscle regeneration; Spiny mouse; Volumetric muscle loss
    DOI:  https://doi.org/10.1186/s13395-024-00358-y
  15. Biomolecules. 2024 Oct 03. pii: 1252. [Epub ahead of print]14(10):
    A Deficiency in Glutamine-Fructose-6-Phosphate Transaminase 1 (Gfpt1) in Skeletal Muscle Results in Reduced Glycosylation of the Delta Subunit of the Nicotinic Acetylcholine Receptor (AChRδ).
    Stephen Henry Holland, Ricardo Carmona-Martinez, Kaela O'Connor, Daniel O'Neil, Andreas Roos, Sally Spendiff, Hanns Lochmüller.
      The neuromuscular junction (NMJ) is the site where the motor neuron innervates skeletal muscle, enabling muscular contraction. Congenital myasthenic syndromes (CMS) arise when mutations in any of the approximately 35 known causative genes cause impaired neuromuscular transmission at the NMJ, resulting in fatigable muscle weakness. A subset of five of these CMS-causative genes are associated with protein glycosylation. Glutamine-fructose-6-phosphate transaminase 1 (Gfpt1) is the rate-limiting enzyme within the hexosamine biosynthetic pathway (HBP), a metabolic pathway that produces the precursors for glycosylation. We hypothesized that deficiency in Gfpt1 expression results in aberrant or reduced glycosylation, impairing the proper assembly and stability of key NMJ-associated proteins. Using both in vitro and in vivo Gfpt1-deficient models, we determined that the acetylcholine receptor delta subunit (AChRδ) has reduced expression and is hypo-glycosylated. Using laser capture microdissection, NMJs were harvested from Gfpt1 knockout mouse muscle. A lower-molecular-weight species of AChRδ was identified at the NMJ that was not detected in controls. Furthermore, Gfpt1-deficient muscle lysates showed impairment in protein O-GlcNAcylation and sialylation, suggesting that multiple glycan chains are impacted. Other key NMJ-associated proteins, in addition to AChRδ, may also be differentially glycosylated in Gfpt1-deficient muscle.
    Keywords:  O-GlcNAcylation; acetylcholine receptor delta subunit (AChRδ); congenital myasthenic syndrome (CMS); glutamine-fructose-6-phosphate transaminase 1 (Gfpt1); glycosylation; neuromuscular junction (NMJ)
    DOI:  https://doi.org/10.3390/biom14101252
  16. Nat Commun. 2024 Oct 25. 15(1): 9218
    Skeletal muscle reprogramming enhances reinnervation after peripheral nerve injury.
    Pihu Mehrotra, James Jablonski, John Toftegaard, Yali Zhang, Shahryar Shahini, Jianmin Wang, Carey W Hung, Reilly Ellis, Gabriella Kayal, Nika Rajabian, Song Liu, Kelly C S Roballo, Susan B Udin, Stelios T Andreadis, Kirkwood E Personius.
      Peripheral Nerve Injuries (PNI) affect more than 20 million Americans and severely impact quality of life by causing long-term disability. PNI is characterized by nerve degeneration distal to the site of nerve injury resulting in long periods of skeletal muscle denervation. During this period, muscle fibers atrophy and frequently become incapable of "accepting" innervation because of the slow speed of axon regeneration post injury. We hypothesize that reprogramming the skeletal muscle to an embryonic-like state may preserve its reinnervation capability following PNI. To this end, we generate a mouse model in which NANOG, a pluripotency-associated transcription factor is expressed locally upon delivery of doxycycline (Dox) in a polymeric vehicle. NANOG expression in the muscle upregulates the percentage of Pax7+ nuclei and expression of eMYHC along with other genes that are involved in muscle development. In a sciatic nerve transection model, NANOG expression leads to upregulation of key genes associated with myogenesis, neurogenesis and neuromuscular junction (NMJ) formation. Further, NANOG mice demonstrate extensive overlap between synaptic vesicles and NMJ acetylcholine receptors (AChRs) indicating restored innervation. Indeed, NANOG mice show greater improvement in motor function as compared to wild-type (WT) animals, as evidenced by improved toe-spread reflex, EMG responses and isometric force production. In conclusion, we demonstrate that reprogramming muscle can be an effective strategy to improve reinnervation and functional outcomes after PNI.
    DOI:  https://doi.org/10.1038/s41467-024-53276-4
  17. Biomolecules. 2024 Sep 25. pii: 1205. [Epub ahead of print]14(10):
    Myokines May Be the Answer to the Beneficial Immunomodulation of Tailored Exercise-A Narrative Review.
    Zheng Lu, Zhuo Wang, Xin-An Zhang, Ke Ning.
      Exercise can regulate the immune function, activate the activity of immune cells, and promote the health of the organism, but the mechanism is not clear. Skeletal muscle is a secretory organ that secretes bioactive substances known as myokines. Exercise promotes skeletal muscle contraction and the expression of myokines including irisin, IL-6, BDNF, etc. Here, we review nine myokines that are regulated by exercise. These myokines have been shown to be associated with immune responses and to regulate the proliferation, differentiation, and maturation of immune cells and enhance their function, thereby serving to improve the health of the organism. The aim of this article is to review the effects of myokines on intrinsic and adaptive immunity and the important role that exercise plays in them. It provides a theoretical basis for exercise to promote health and provides a potential mechanism for the correlation between muscle factor expression and immunity, as well as the involvement of exercise in body immunity. It also provides the possibility to find a suitable exercise training program for immune system diseases.
    Keywords:  exercise; immune cells; myokines; skeletal muscle
    DOI:  https://doi.org/10.3390/biom14101205
  18. Mol Med. 2024 Oct 25. 30(1): 185
    Skeletal myotubes expressing ALS mutant SOD1 induce pathogenic changes, impair mitochondrial axonal transport, and trigger motoneuron death.
    Pablo Martínez, Mónica Silva, Sebastián Abarzúa, María Florencia Tevy, Enrique Jaimovich, Martha Constantine-Paton, Fernando J Bustos, Brigitte van Zundert.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons (MNs), and despite progress, there is no effective treatment. A large body of evidence shows that astrocytes expressing ALS-linked mutant proteins cause non-cell autonomous toxicity of MNs. Although MNs innervate muscle fibers and ALS is characterized by the early disruption of the neuromuscular junction (NMJ) and axon degeneration, there are controversies about whether muscle contributes to non-cell-autonomous toxicity to MNs. In this study, we generated primary skeletal myotubes from myoblasts derived from ALS mice expressing human mutant SOD1G93A (termed hereafter mutSOD1). Characterization revealed that mutSOD1 skeletal myotubes display intrinsic phenotypic and functional differences compared to control myotubes generated from non-transgenic (NTg) littermates. Next, we analyzed whether ALS myotubes exert non-cell-autonomous toxicity to MNs. We report that conditioned media from mutSOD1 myotubes (mutSOD1-MCM), but not from control myotubes (NTg-MCM), induced robust death of primary MNs in mixed spinal cord cultures and compartmentalized microfluidic chambers. Our study further revealed that applying mutSOD1-MCM to the MN axonal side in microfluidic devices rapidly reduces mitochondrial axonal transport while increasing Ca2 + transients and reactive oxygen species (i.e., H2O2). These results indicate that soluble factor(s) released by mutSOD1 myotubes cause MN axonopathy that leads to lethal pathogenic changes.
    Keywords:  ALS; Axonopathy; Mitochondria; Motoneuron; Muscle; Myotubes; Pathology
    DOI:  https://doi.org/10.1186/s10020-024-00942-4
  19. Int J Mol Sci. 2024 Oct 10. pii: 10877. [Epub ahead of print]25(20):
    Recent Advances of Exosomes Derived from Skeletal Muscle and Crosstalk with Other Tissues.
    Jia Luo, Qiang Pu, Xiaoqian Wu.
      Skeletal muscle plays a crucial role in movement, metabolism, and energy homeostasis. As the most metabolically active endocrine organ in the body, it has recently attracted widespread attention. Skeletal muscle possesses the ability to release adipocytokines, bioactive peptides, small molecular metabolites, nucleotides, and other myogenic cell factors; some of which have been shown to be encapsulated within small vesicles, particularly exosomes. These skeletal muscle exosomes (SKM-Exos) are released into the bloodstream and subsequently interact with receptor cell membranes to modulate the physiological and pathological characteristics of various tissues. Therefore, SKM-Exos may facilitate diverse interactions between skeletal muscle and other tissues while also serving as biomarkers that reflect the physiological and pathological states of muscle function. This review delves into the pivotal role and intricate molecular mechanisms of SKM-Exos and its derived miRNAs in the maturation and rejuvenation of skeletal muscle, along with their intercellular signaling dynamics and physiological significance in interfacing with other tissues.
    Keywords:  adipose; bone; crosstalk; exosome; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms252010877
  20. Mol Neurobiol. 2024 Oct 31.
    Astragaloside IV Improves Muscle Atrophy by Modulating the Activity of UPS and ALP via Suppressing Oxidative Stress and Inflammation in Denervated Mice.
    Hua Liu, Kexin Wang, Tongxin Shang, Zhigang Cai, Chunfeng Lu, Mi Shen, Shu Yu, Xinlei Yao, Yuntian Shen, Xiaofang Chen, Feng Xu, Hualin Sun.
      Peripheral nerve injury is common clinically and can lead to neuronal degeneration and atrophy and fibrosis of the target muscle. The molecular mechanisms of muscle atrophy induced by denervation are complex and not fully understood. Inflammation and oxidative stress play an important triggering role in denervated muscle atrophy. Astragaloside IV (ASIV), a monomeric compound purified from astragalus membranaceus, has antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effect of ASIV on denervated muscle atrophy and its molecular mechanism, so as to provide a new potential therapeutic target for the prevention and treatment of denervated muscle atrophy. In this study, an ICR mouse model of muscle atrophy was generated through sciatic nerve dissection. We found that ASIV significantly inhibited the reduction of tibialis anterior muscle mass and muscle fiber cross-sectional area in denervated mice, reducing ROS and oxidative stress-related protein levels. Furthermore, ASIV inhibits the increase in inflammation-associated proteins and infiltration of inflammatory cells, protecting the denervated microvessels in skeletal muscle. We also found that ASIV reduced the expression levels of MAFbx, MuRF1 and FoxO3a, while decreasing the expression levels of autophagy-related proteins, it inhibited the activation of ubiquitin-proteasome and autophagy-lysosome hydrolysis systems and the slow-to-fast myofiber shift. Our results show that ASIV inhibits oxidative stress and inflammatory responses in skeletal muscle due to denervation, inhibits mitophagy and proteolysis, improves microvascular circulation and reverses the transition of muscle fiber types; Therefore, the process of skeletal muscle atrophy caused by denervation can be effectively delayed.
    Keywords:  ASIV; Denervated muscle atrophy; Inflammatory response; Oxidative stress
    DOI:  https://doi.org/10.1007/s12035-024-04590-x
  21. Eur J Transl Myol. 2024 Oct 29.
    An aged-related structural study of DHPR tetrads in peripheral couplings of human skeletal muscle.
    Laura Pietrangelo, Rosa Mancinelli, Stefania Fulle, Simona Boncompagni.
      Among the numerous changes that occur in skeletal muscle during aging, the reduced regeneration potential after an injury is largely due to the impaired ability of satellite cells to proliferate and differentiate. Herein, using the freeze-fracture electron microscopy technique, we analyzed both the incidence and size of dihydropyridine receptors (DHPRs) tetrads (4 particles) in cultured myotubes from a young subject (28 years) after 9 days of differentiation and from an old subject (71 years) after 9 and 12 days of differentiation. Compared to young myotubes, at 9 days of differentiation old myotubes exhibited: i) a lower incidence and a smaller size of DHPR clusters and ii) a lower number of complete tetrads. At 12 days of differentiation values of incidence, size and number of complete tetrads in old myotubes were instead comparable with those of young myotubes at 9 days of differentiation. Collectively, these results indicate that in aged myotubes the synthesis process of the proteins involved in the excitation-contraction coupling mechanism, such as the DHPR, is somehow slowed, supporting previous studies evidence of a decrease in the differentiation potential of myotubes from elderly individuals.
    DOI:  https://doi.org/10.4081/ejtm.2024.13273
  22. Front Cell Dev Biol. 2024 ;12 1481491
    Cellular and transcriptomic changes by the supplementation of aged rat serum in human pluripotent stem cell-derived myogenic progenitors.
    Sin-Ruow Tey, Ryan S Anderson, Clara H Yu, Samantha Robertson, Heidi Kletzien, Nadine P Connor, Kaori Tanaka, Yasuyuki Ohkawa, Masatoshi Suzuki.
       Introduction: The changing composition of non-cell autonomous circulating factors in blood as humans age is believed to play a role in muscle mass and strength loss. The mechanisms through which these circulating factors act in age-related skeletal muscle changes is not fully understood. In this study, we used human myogenic progenitors derived from human pluripotent stem cells to study non-cell autonomous roles of circulating factors during the process of myogenic differentiation.
    Methods: Myogenic progenitors from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) were supplemented with serum samples from aged or young Fischer 344 × Brown Norway F1-hybrid rats. The effect of aged or young serum supplementation on myogenic progenitor proliferation, myotube formation capacity, differentiation, and early transcriptomic profiles were analyzed.
    Results: We found that aged rat serum supplementation significantly reduced cell proliferation and increased cell death in both ESC- and iPSC-derived myogenic progenitors. Next, we found that the supplementation of aged rat serum inhibited myotube formation and maturation during terminal differentiation from progenitors to skeletal myocytes when compared to the cells treated with young adult rat serum. Lastly, we identified that gene expression profiles were affected following serum supplementation in culture.
    Discussion: Together, aged serum supplementation caused cellular and transcriptomic changes in human myogenic progenitors. The current data from our in vitro model possibly simulate non-cell autonomous contributions of blood composition to age-related processes in human skeletal muscle.
    Keywords:  F344/BN rat serum; human pluripotent stem cells; myogenic progenitors; sarcopenia; skeletal muscle aging
    DOI:  https://doi.org/10.3389/fcell.2024.1481491
  23. J Cell Biol. 2025 Jan 06. pii: e202404052. [Epub ahead of print]224(1):
    Postsynaptic BMP signaling regulates myonuclear properties in Drosophila larval muscles.
    Victoria E von Saucken, Stefanie E Windner, Giovanna Armetta, Mary K Baylies.
      The syncytial mammalian muscle fiber contains a heterogeneous population of (myo)nuclei. At the neuromuscular junction (NMJ), myonuclei have specialized positioning and gene expression. However, it remains unclear how myonuclei are recruited and what regulates myonuclear output at the NMJ. Here, we identify specific properties of myonuclei located near the Drosophila larval NMJ. These synaptic myonuclei have increased size in relation to their surrounding cytoplasmic domain (size scaling), increased DNA content (ploidy), and increased levels of transcription factor pMad, a readout for BMP signaling activity. Our genetic manipulations show that local BMP signaling affects muscle size, nuclear size, ploidy, and NMJ size and function. In support, RNA sequencing analysis reveals that pMad regulates genes involved in muscle growth, ploidy (i.e., E2f1), and neurotransmission. Our data suggest that muscle BMP signaling instructs synaptic myonuclear output that positively shapes the NMJ synapse. This study deepens our understanding of how myonuclear heterogeneity supports local signaling demands to fine tune cellular function and NMJ activity.
    DOI:  https://doi.org/10.1083/jcb.202404052
  24. Brain. 2024 Oct 26. pii: awae336. [Epub ahead of print]
    MBNL deficiency in motor neurons disrupts neuromuscular junction maintenance and gait coordination.
    Charles Frison-Roche, Célia Martin Demier, Steve Cottin, Jeanne Lainé, Ludovic Arandel, Marius Halliez, Mégane Lemaitre, Xavière Lornage, Laure Strochlic, Maurice S Swanson, Cécile Martinat, Julien Messéant, Denis Furling, Frédérique Rau.
      Muscleblind-like proteins (MBNLs) are a family of RNA-binding proteins that play essential roles in the regulation of RNA metabolism. Beyond their canonical role in RNA regulation, MBNL proteins have emerged as key players in the pathogenesis of Myotonic Dystrophy type 1 (DM1). In DM1, sequestration of MBNL proteins by expansion of the CUG repeat RNA leads to functional depletion of MBNL, resulting in deregulated alternative splicing and aberrant RNA processing, which underlie the clinical features of the disease. While attention to MBNL proteins has focused on their functions in skeletal muscle, new evidence suggests that their importance extends to motor neurons (MNs), pivotal cellular components in the control of motor skills and movement. To address this question, we generated conditional double knockout mice in which Mbnl1 and Mbnl2 were specifically deleted in motor neurons (MN-dKO). Adult MN-dKO mice develop gait coordination deficits associated with structural and ultrastructural defects in the neuromuscular junction, indicating that MBNL activity in MNs is crucial for the maintenance of the neuromuscular junction. In addition, transcriptome analysis performed on the spinal cord of MN-dKO mice identified mis-splicing events in genes associated with synaptic transmission and neuromuscular junction homeostasis. In summary, our results highlight the complex roles and regulatory mechanisms of MBNL proteins in MNs for muscle function and locomotion. This work provides valuable insights into fundamental aspects of RNA biology and offers promising avenues for therapeutic intervention in DM1 as well as a range of diseases associated with RNA dysregulation.
    Keywords:  DM1; MBNL; RNA binding protein; alternative splicing; motor neurons; neuromuscular junction
    DOI:  https://doi.org/10.1093/brain/awae336
  25. Am J Physiol Cell Physiol. 2024 Oct 28.
    Transcriptional Analysis of Cancer Cachexia: Conserved and Unique Features Across Pre-Clinical Models and Biological Sex.
    Francielly Morena, Ana Regina Cabrera, Ronald G Jones Iii, Eleanor R Schrems, Ruqaiza Muhyudin, Tyrone A Washington, Kevin A Murach, Nicholas P Greene.
      Studies suggest heterogeneity in cancer cachexia (CC) among models and biological sexes, yet examinations comparing models and sexes are scarce. We compared the transcriptional landscape of skeletal muscle across murine CC models and biological sexes during early and late CC. Global gene expression analyses were performed on gastrocnemius (LLC-Lewis Lung Carcinoma), quadriceps (KPC-pancreatic), and tibialis anterior (C26-colorectal and ApcMin/+) muscles across biological sexes. Differentially expressed genes (DEGs) were identified using an adj-p-value of <0.05, followed by pathway and computational cistrome analyses. Integrating all controls, early, and late-stage of all models and sexes revealed up to 68% of DEGs and pathways were enriched at early and late CC, indicating a conserved transcriptional profile during CC development. Comparing DEGs and pathways within sexes and across models, in early-CC, the transcriptional response was highly heterogeneous. At late-stage, 11.5% of upregulated and 10% of downregulated genes were shared between models in males, while 18.9% of upregulated and 7% of downregulated DEGs were shared in females. Shared DEGs were enriched in proteasome and mitophagy/autophagy pathways (upregulated), and downregulation of energy metabolism pathways in males only. Between sexes, though proportion of shared DEGs was low (<16%), similar pathway enrichment was observed, including proteasome and mitophagy at late-stage CC. In early-CC, Osmr upregulation was the only commonality across all models and sexes, while CLOCK and ARNTL/BMAL1 were predicted transcriptional factors associated with dysregulations in all three male models. This study highlights sex and model differences in CC progression and suggests conserved transcriptional changes as potential therapeutic targets.
    Keywords:  RNA-sequencing; colon cancer; heterogeneity; lung cancer; pancreatic cancer
    DOI:  https://doi.org/10.1152/ajpcell.00647.2024
  26. Acta Myol. 2024 Sep;43(3): 89-94
    Abnormal expression of myosin heavy chains in early postnatal stages of spinal muscular atrophy type I at single fibre level.
    Carola Hedberg-Oldfors, Elizabeth Jennions, Kittichate Visuttijai, Anders Oldfors.
       Objective: We investigated myosin heavy chain (MyHC) isoform expression at early postnatal stages of clinically and genetically confirmed spinal muscular atrophy type 1 (SMA1) patients, in order to study the muscle fibre differentiation compared to age-matched controls at single fibre level.
    Methods: Open skeletal muscle biopsies were performed from the quadriceps muscle in four SMA1 patients and three age-matched controls. Standard techniques were used for immunohistochemistry of embryonic and foetal MyHCs. Type I, IIa and IIx MyHCs were assessed by applying quadruple immunofluorescence. Western blot was performed to analyse the amount of survival motor neuron (SMN) protein in the muscle samples.
    Results: There were profound and early alterations in MyHC expression from 7 days of life compared to age-matched controls. The expression of type IIx MyHC was completely lost in SMA1 and instead developmental isoforms remained highly expressed. Foetal MyHC was still, at 3.5 months of age, expressed in the majority of muscle fibres in SMA1 patients, whereas it was completely downregulated in age-matched controls. The level of SMN protein was reduced in all SMN1 patients.
    Conclusions: The abnormal pattern of MyHC expression in postnatal stages of SMA1 was observed early in the newborn period, which may have implications for the effects of gene therapy, since there are clear clinical benefits from early treatment. Whether such aberrant and delayed expression of MyHCs can be completely restored by postnatal gene therapy remains to be studied and may also have implications for new phenotypes that will evolve with new therapies.
    Keywords:  MyHC isoforms; SMA; myosin; single fibre; spinal muscular atrophy
    DOI:  https://doi.org/10.36185/2532-1900-558
  27. Exp Neurol. 2024 Oct 24. pii: S0014-4886(24)00351-0. [Epub ahead of print]383 115025
    Ighmbp2 mutations and disease pathology: Defining differences that differentiate SMARD1 and CMT2S.
    Sara M Ricardez Hernandez, Bassil Ahmed, Yaser Al Rawi, F Javier Llorente Torres, Mona O Garro Kacher, Catherine L Smith, Zayd Al Rawi, Jessica Garcia, Nicole L Nichols, Christian L Lorson, Monique A Lorson.
      Mutations in the Immunoglobulin mu DNA binding protein 2 (IGHMBP2) gene result in two distinct diseases, SMA with Respiratory Distress Type I (SMARD1) and Charcot Marie Tooth Type 2S (CMT2S). To understand the phenotypic and molecular differences between SMARD1 and CMT2S, and the role of IGHMBP2 in disease development, we generated mouse models based on six IGHMBP2 patient mutations. Previously, we reported the development and characterization of Ighmbp2D564N/D564N mice and in this manuscript, we examine two mutations: D565N (D564N in mice) and H924Y (H922Y in mice) in the Ighmbp2H922Y/H922Y and Ighmbp2D564N/H922Y contexts. We found significant differences between these mouse models, providing critical insight into the role of IGHMBP2 in the pathogenesis of SMARD1 and CMT2S. Importantly, these studies also demonstrate how disease pathogenesis is significantly altered in the context of Ighmbp2 D564N and H922Y homozygous recessive and compound heterozygous mutations. Notably, there were short-lived and long-lived lifespan cohorts within Ighmbp2D564N/H922Y mice with early (P12/P16) respiratory pathology serving as a key predictor of lifespan. Despite differences in lifespan, motor function deficits initiated early and progressively worsened in all Ighmbp2D564N/H922Y mice. There was decreased limb skeletal muscle fiber area and increased neuromuscular junction (NMJ) denervation in Ighmbp2D564N/H922Y mice. Consistent with CMT2S, Ighmbp2H922Y/H922Y mice did not have altered lifespans nor respiratory pathology. Interestingly, Ighmbp2H922Y/H922Y limb muscle fibers demonstrated an increase in muscle fiber area followed by a reduction while changes in NMJ innervation were minimal even at P180. This is the first study that demonstrates differences associated with IGHMBP2 function within respiration with those within limb motor function. Significant to our understanding of IGHMBP2 function, we demonstrate that there is a direct correlation between disease pathogenesis associated with these IGHMBP2 patient mutations and IGHMBP2 biochemical activity. Importantly, these studies reveal the dynamic differences that are presented when either a single mutant protein is present (IGHMBP2-D564N or IGHMBP2-H922Y) or two mutant proteins are present (IGHMBP2-D564N and IGHMBP2-H922Y) within cells.
    Keywords:  IGHMBP2; Mouse models; Neurodegeneration; Respiration; SMARD1/CMT2S
    DOI:  https://doi.org/10.1016/j.expneurol.2024.115025
  28. Int J Mol Sci. 2024 Oct 21. pii: 11310. [Epub ahead of print]25(20):
    The Gut Microbiota Involvement in the Panorama of Muscular Dystrophy Pathogenesis.
    Cristina Russo, Sofia Surdo, Maria Stella Valle, Lucia Malaguarnera.
      Muscular dystrophies (MDs) are genetically heterogeneous diseases characterized by primary skeletal muscle atrophy. The collapse of muscle structure and irreversible degeneration of tissues promote the occurrence of comorbidities, including cardiomyopathy and respiratory failure. Mitochondrial dysfunction leads to inflammation, fibrosis, and adipogenic cellular infiltrates that exacerbate the symptomatology of MD patients. Gastrointestinal disorders and metabolic anomalies are common in MD patients and may be determined by the interaction between the intestine and its microbiota. Therefore, the gut-muscle axis is one of the actors involved in the spread of inflammatory signals to all muscles. In this review, we aim to examine in depth how intestinal dysbiosis can modulate the metabolic state, the immune response, and mitochondrial biogenesis in the course and progression of the most investigated MDs such as Duchenne Muscular Dystrophy (DMD) and Myotonic Dystrophy (MD1), to better identify gut microbiota metabolites working as therapeutic adjuvants to improve symptoms of MD.
    Keywords:  gut–muscle axis; intestinal microbiota; intestinal microbiota-derived metabolites; mitochondrial muscle biogenesis; muscular dystrophies; muscular immunity
    DOI:  https://doi.org/10.3390/ijms252011310
  29. Mol Metab. 2024 Oct 28. pii: S2212-8778(24)00189-3. [Epub ahead of print] 102058
    Macrophages on the Run: exercise balances macrophage polarization for improved health.
    Yotam Voskoboynik, Andrew D McCulloch, Debashis Sahoo.
       OBJECTIVE: Exercise plays a crucial role in maintaining and improving human health. However, the precise molecular mechanisms that govern the body's response to exercise or/compared to periods of inactivity remain elusive. Current evidence appears to suggest that exercise exerts a seemingly dual influence on macrophage polarization states, inducing both pro-immune response M1 activation and cell-repair-focused M2 activation. To reconcile this apparent paradox, we leveraged a comprehensive meta-analysis of 75 diverse exercise and immobilization published datasets (7000+ samples), encompassing various exercise modalities, sampling techniques, and species.
    METHODS: 75 exercise and immobilization expression datasets were identified and processed for analysis. The data was analyzed using boolean relationships which uses binary gene expression relationships in order to increase the signal to noise achieved from the data, allowing for the use of comparison across such a diverse set of datasets. We utilized a boolean relationship-aided macrophage gene model [1], to model the macrophage polarization state in pre and post exercise samples in both immediate exercise and long term training.
    RESULTS: Our modeling uncovered a key temporal dynamic: exercise triggers an immediate M1 surge, while long term training transitions to sustained M2 activation. These patterns were consistent across different species (human vs mouse), sampling methods (blood vs muscle biopsy), and exercise type (resistance vs endurance), and routinely showed statistically significant results. Immobilization was shown to have the opposite effect of exercise by triggering an immediate M2 activation. Individual characteristics like gender, exercise intensity and age were found to impact the degree of polarization without changing the overall patterns. To model macrophages within the specific context of muscle tissue, we identified a focused gene set signature of muscle resident macrophage polarization, allowing for the precise measurement of macrophage activity in response to exercise within the muscle.
    CONCLUSIONS: These consistent patterns across all 75 examined studies suggest that the long term health benefits of exercise stem from its ability to orchestrate a balanced and temporally-regulated interplay between pro-immune response (M1) and reparative macrophage activity (M2). Similarly, it suggests that an imbalance between pro-immune and cell repair responses could facilitate disease development. Our findings shed light on the intricate molecular choreography behind exercise-induced health benefits with a particular insight on its effect on the macrophages within the muscle.
    Keywords:  Exercise Biology; Immune Modulation; Machine Learning Models; Macrophage Polarization; Muscle; Tissue Regeneration
    DOI:  https://doi.org/10.1016/j.molmet.2024.102058
  30. Int J Mol Sci. 2024 Oct 16. pii: 11095. [Epub ahead of print]25(20):
    The Effect of Lower Limb Combined Neuromuscular Electrical Stimulation on Skeletal Muscle Cross-Sectional Area and Inflammatory Signaling.
    Amal Alharbi, Jia Li, Erika Womack, Matthew Farrow, Ceren Yarar-Fisher.
      In individuals with a spinal cord injury (SCI), rapid skeletal muscle atrophy and metabolic dysfunction pose profound rehabilitation challenges, often resulting in substantial loss of muscle mass and function. This study evaluates the effect of combined neuromuscular electrical stimulation (Comb-NMES) on skeletal muscle cross-sectional area (CSA) and inflammatory signaling within the acute phase of SCI. We applied a novel Comb-NMES regimen, integrating both high-frequency resistance and low-frequency aerobic protocols on the vastus lateralis muscle, to participants early post-SCI. Muscle biopsies were analyzed for CSA and inflammatory markers pre- and post-intervention. The results suggest a potential preservation of muscle CSA in the Comb-NMES group compared to a control group. Inflammatory signaling proteins such as TLR4 and Atrogin-1 were downregulated, whereas markers associated with muscle repair and growth were modulated beneficially in the Comb-NMES group. The study's findings suggest that early application of Comb-NMES post-SCI may attenuate inflammatory pathways linked to muscle atrophy and promote muscle repair. However, the small sample size and variability in injury characteristics emphasize the need for further research to corroborate these results across a more diverse and extensive SCI population.
    Keywords:  inflammatory signaling; muscle cross-sectional area; myofiber adaptation; neuromuscular electrical stimulation; spinal cord injury
    DOI:  https://doi.org/10.3390/ijms252011095
  31. Nat Metab. 2024 Oct 31.
    Skeletal muscle from TBC1D4 p.Arg684Ter variant carriers is severely insulin resistant but exhibits normal metabolic responses during exercise.
    Jonas M Kristensen, Rasmus Kjøbsted, Trine J Larsen, Christian S Carl, Janne R Hingst, Johan Onslev, Jesper B Birk, Anette Thorup, Dorte E Steenberg, Jonas R Knudsen, Nicolai S Henriksen, Elise J Needham, Jens F Halling, Anders Gudiksen, Carsten F Rundsten, Kristian E Hanghøj, Sara E Stinson, Birgitte Hoier, Camilla C Hansen, Thomas E Jensen, Ylva Hellsten, Henriette Pilegaard, Niels Grarup, Jesper Olesen, Sean J Humphrey, David E James, Michael L Pedersen, Erik A Richter, Torben Hansen, Marit E Jørgensen, Jørgen F P Wojtaszewski.
      In the Greenlandic Inuit population, 4% are homozygous carriers of a genetic nonsense TBC1D4 p.Arg684Ter variant leading to loss of the muscle-specific isoform of TBC1D4 and an approximately tenfold increased risk of type 2 diabetes1. Here we show the metabolic consequences of this variant in four female and four male homozygous carriers and matched controls. An extended glucose tolerance test reveals prolonged hyperglycaemia followed by reactive hypoglycaemia in the carriers. Whole-body glucose disposal is impaired during euglycaemic-hyperinsulinaemic clamp conditions and associates with severe insulin resistance in skeletal muscle only. Notably, a marked reduction in muscle glucose transporter GLUT4 and associated proteins is observed. While metabolic regulation during exercise remains normal, the insulin-sensitizing effect of a single exercise bout is compromised. Thus, loss of the muscle-specific isoform of TBC1D4 causes severe skeletal muscle insulin resistance without baseline hyperinsulinaemia. However, physical activity can ameliorate this condition. These observations offer avenues for personalized interventions and targeted preventive strategies.
    DOI:  https://doi.org/10.1038/s42255-024-01153-1
  32. Acta Biomater. 2024 Oct 23. pii: S1742-7061(24)00625-1. [Epub ahead of print]
    Ionic medicine: exploiting metallic ions to stimulate skeletal muscle tissue regeneration.
    Hsuan-Heng Lu, Duygu Ege, Sahar Salehi, Aldo R Boccaccini.
      The regeneration of healthy and functional skeletal muscle at sites of injuries and defects remains a challenge. Mimicking the natural environment surrounding skeletal muscle cells and the application of electrical and mechanical stimuli are approaches being investigated to promote muscle tissue regeneration. Likewise, chemical stimulation with therapeutic (biologically active) ions is an emerging attractive alternative in the tissue engineering and regenerative medicine fields, specifically to trigger myoblast proliferation, myogenic differentiation, myofiber formation, and ultimately to promote new muscle tissue growth. The present review covers the specialized literature focusing on the biochemical stimulation of muscle tissue repair by applying inorganic ions (bioinorganics). Extracting information from the literature, different ions and their potential influence as chemical cues on skeletal muscle regeneration are discussed. It is revealed that different ions and their varied doses have an individual effect at different stages of muscle cellular development. The dose-dependent effects of ions, as well as applications of ions alone and in combination with biomaterials, are also summarized. Some ions, such as boron, silicon, magnesium, and zinc, are reported to exhibit a beneficial effect on skeletal muscle cells in carefully controlled doses, while the effects of other ions such as iron and copper appear to be contradictory. In addition, calcium is an essential regulatory ion for the differentiation of myoblasts. On the other hand, some ions such as phosphate have been shown to inhibit muscle cell behaviour. It is expected that this review will provide a complete overview of the application of ionic stimulation for skeletal muscle tissue engineering applications, and will highlight the importance of inorganic ions as an attractive alternative to the application of small molecules and growth factors to stimulate muscle tissue repair. STATEMENT OF SIGNIFICANCE: Ionic medicine (IM) is emerging as a promising and attractive approach in the field of tissue engineering, including muscle tissue regeneration. IM is based on the delivery of biologically active ions to injury sites, acting as stimulants for the repair process. This method offers a potentially simpler and more affordable alternative to conventional biomolecule-based regulators such as growth factors. Different biologically active ions, depending on their specific doping concentrations, can have varying effects on cellular development, which could be either beneficial or inhibitory. This literature review covers the field of IM in muscle regeneration with focus on the impact of various ions on skeletal muscle regeneration. The paper is thus a critical summary for guiding future research in ionic-related regenerative medicine, highlighting the potential and challenges of this approach for muscle regeneration.
    Keywords:  Ions; ionic medicine; muscle regeneration; skeletal muscle
    DOI:  https://doi.org/10.1016/j.actbio.2024.10.033
  33. Med Sci Sports Exerc. 2024 Nov 01. 56(11): 2125-2134
    The Effect of Multi-Ingredient Protein versus Collagen Supplementation on Satellite Cell Properties in Males and Females.
    Mai Wageh, Stephen A Fortino, Riley Pontello, Ahmed Maklad, Chris McGlory, Dinesh Kumbhare, Stuart M Phillips, Gianni Parise.
       INTRODUCTION: Skeletal muscle satellite cells (SC) contribute to the adaptive process of resistance exercise training (RET) and may be influenced by nutritional supplementation. However, little research exists on the impact of multi-ingredient supplementation on the SC response to RET.
    PURPOSE: We tested the effect of a multi-ingredient supplement (MIS) including whey protein, creatine, leucine, calcium citrate, and vitamin D on SC content and activity as well as myonuclear accretion, SC and myonuclear domain compared with a collagen control (COL) throughout a 10-wk RET program.
    METHODS: Twenty-six participants underwent a 10-wk linear RET program while consuming either the MIS or COL supplement twice daily. Muscle biopsies were taken from the vastus lateralis at baseline and 48 h after a bout of damaging exercise, before and after RET. Muscle tissue was analyzed for SC and myonuclear content, domain, acute SC activation, and fiber cross-sectional area (fCSA).
    RESULTS: MIS resulted in a greater increase in type II fCSA following 10 wk of RET (effect size (ES) = 0.89) but not myonuclear accretion or SC content. Change in myonuclei per fiber was positively correlated with type I and II and total fiber hypertrophy in the COL group only, indicating a robust independent effect of MIS on fCSA. Myonuclear domain increased similarly in both groups, whereas SC domain remained unchanged following RET. SC activation was similar between groups for all fiber types in the untrained state but showed a trend toward greater increases with MIS after RET (ES = 0.70).
    CONCLUSIONS: SC responses to acute damaging exercise and long-term RET are predominantly similar in MIS and COL groups. However, MIS can induce greater increases in type II fCSA with RET and potentially SC activation following damage in the trained state.
    DOI:  https://doi.org/10.1249/MSS.0000000000003505
  34. Clin Exp Pharmacol Physiol. 2024 Dec;51(12): e70001
    Short-term exercise counteracts accelerated ageing impacts on physical performance and liver health in mice.
    Ana P Pinto, Vitor R Muñoz, Maria Eduarda A Tavares, Ivo V de Sousa Neto, Jonathas R Dos Santos, Guilherme S Rodrigues, Ruither O Gomes Carolino, Luciane C Alberici, Fernando M Simabuco, Giovana R Teixeira, José R Pauli, Leandro P de Moura, Dennys E Cintra, Eduardo R Ropelle, Ellen C Freitas, Donato A Rivas, Adelino S R da Silva.
      Senescence impairs liver physiology, mitochondrial function and circadian regulation, resulting in systemic metabolic dysregulation. Given the limited research on the effects of combined exercise on an ageing liver, this study aimed to evaluate its impact on liver metabolism, circadian rhythms and mitochondrial function in senescence-accelerated mouse-prone 8 (SAMP8) and senescence-accelerated mouse-resistant 1 (SAMR1) mice. Histological, reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunoblotting analyses were conducted, supplemented by transcriptomic data sets and AML12 hepatocyte studies. Sedentary SAMP8 mice exhibited decreased muscle strength, reduced mitochondrial complex I levels and increased lipid droplet accumulation. In contrast, combined exercise mitigated muscle strength loss, upregulated proteins involved in mitochondrial complexes (CIII, CIV, CV) and increased Bmal1 messenger RNA (mRNA) expression in the liver. These molecular adaptations are associated with healthier liver phenotypes and may influence metabolic function and cellular longevity. Notably, elevated lipid content in aged mice was reduced post-exercise, indicating liver benefits even after a relatively short intervention. The combined exercise regimen did not improve aerobic capacity, likely due to the low volume and brief duration of running. Moreover, no significant effects were observed in SAMR1 mice, possibly because the training intensity was insufficient for younger, healthier animals. These findings underscore the potential of combined strength and endurance exercise to attenuate age-related liver dysfunction, particularly in ageing populations.
    Keywords:  aging; exercise; lipid droplet; liver; senescence
    DOI:  https://doi.org/10.1111/1440-1681.70001
  35. Int J Mol Sci. 2024 Oct 21. pii: 11317. [Epub ahead of print]25(20):
    SAT1/ALOX15 Signaling Pathway Is Involved in Ferroptosis After Skeletal Muscle Contusion.
    Huihuang Yang, Yingmin Li, Weihao Zhu, Xiaowei Feng, Hongjian Xin, Hao Chen, Guozhong Zhang, Min Zuo, Bin Cong, Weibo Shi.
      Skeletal muscle contusion (SMC) is common in daily life and clinical practice, but the molecular mechanisms underlying SMC healing are unclear. Ferroptosis, a regulated cell death type, has gained attention recently. We observed iron overload in skeletal muscle following contusion through HE and Perls staining. Abnormal iron levels are highly likely to induce ferroptosis. Therefore, we aimed to explore whether iron overload after contusion leads to ferroptosis in skeletal muscle and the underlying mechanisms, which will help us understand the effects of iron abnormalities on skeletal muscle repair. Initially, we searched SMC gene expression profiles from the GEO database and used bioinformatics analysis to reveal ferroptosis occurrence. Then, we identified the gene sat1 plays an important role in this process. We further established a rat SMC model and treated rats with ferroptosis inhibitors (Ferrostatin-1, Deferoxamine). Our findings confirmed iron overload from SMC can lead to ferroptosis in rats. We also demonstrated that SAT1 can regulate ferroptosis by affecting ALOX15. Moreover, we constructed a ferroptosis L6 cell model and found that SAT1 knockdown significantly inhibited ALOX15 expression and reduced cellular lipid peroxidation. In conclusion, these results indicated ferroptosis can occur following SMC, and SAT1, as a key regulator, affects skeletal muscle injury healing by mediating high ALOX15 expression, which in turn regulates lipid peroxidation.
    Keywords:  ALOX15; SAT1; contusion; ferroptosis; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms252011317
  36. J Physiol. 2024 Oct 28.
    Neuromuscular mechanisms for the fast decline in rate of force development with muscle disuse - a narrative review.
    Luca Ruggiero, Markus Gruber.
      The removal of skeletal muscle tension (unloading or disuse) is followed by many changes in the neuromuscular system, including muscle atrophy and loss of isometric maximal strength (measured by maximal force, Fmax). Explosive strength, i.e. the ability to develop the highest force in the shortest possible time, to maximise rate of force development (RFD), is a fundamental neuromuscular capability, often more functionally relevant than maximal muscle strength. In the present review, we discuss data from studies that looked at the effect of muscle unloading on isometric maximal versus explosive strength. We present evidence that muscle unloading yields a greater decline in explosive relative to maximal strength. The longer the unloading duration, the smaller the difference between the decline in the two measures. Potential mechanisms that may explain the greater decline in measures of RFD relative to Fmax after unloading are higher recruitment thresholds and lower firing rates of motor units, slower twitch kinetics, impaired excitation-contraction coupling, and decreased tendon stiffness. Using a Hill-type force model, we showed that this ensemble of adaptations minimises the loss of force production at submaximal contraction intensities, at the expense of a disproportionately lower RFD. With regard to the high functional relevance of RFD on one hand, and the boosted detrimental effects of inactivity on RFD on the other hand, it seems crucial to implement specific exercises targeting explosive strength in populations that experience muscle disuse over a longer time.
    Keywords:  bed rest; explosive strength; limb immobilisation; muscle disuse; rate of force development; unilateral lower limb suspension; unloading
    DOI:  https://doi.org/10.1113/JP285667
  37. Adv Healthc Mater. 2024 Oct 28. e2402991
    Engineering Nanoclusters of Cell Adhesive Ligands on Biomaterial Surfaces: Superior Cell Proliferation and Myotube Formation for Skeletal Muscle Tissue Regeneration.
    Shirin Nour, Sadegh Shabani, Kristy Swiderski, Gordon S Lynch, Andrea J O'Connor, Greg Qiao, Daniel E Heath.
      Engineering biointerfaces with nanoscale clustering of integrin-binding cell adhesive peptides is critical for promoting receptor redistribution into signaling complexes. Skeletal muscle cells are exquisitely sensitive to integrin-mediated signaling, yet biomaterials supporting myogenesis through control of the density and nanodistribution of ligands have not been developed. Here, materials are developed with tailorable cell adhesive ligands distribution at the interface by independently controlling their global and local density to enhance myogenesis, by promoting myoblast growth and myotube formation. To this end, RGD-functionalized low-fouling polymer surfaces with global ligand densities (G) from 0-7 µg peptide/mg polymer and average local ligand densities (L) from 1-6.3 ligands/cluster, are generated and characterized. Cell studies demonstrate improvements in cell adhesion, spreading, growth, and myotube formation up to a density of 7 µg peptide/mg polymer with 4 ligands/cluster. Optimizing ligand density and distribution also promotes early myofiber maturation, identified by increased MF20 marker protein expression and sarcomere-forming myotubes. At higher ligand densities, these cell properties are decreased, indicating that ligand multivalency is a critical parameter for tailoring cell-material interactions, to a certain threshold. The findings provide new insights for designing next-generation biomaterials and hold promise for improved engineering of skeletal muscle.
    Keywords:  biointerface; muscle tissue regeneration; myoblasts; nanoengineering; peptide functionalisation
    DOI:  https://doi.org/10.1002/adhm.202402991
  38. Sci Rep. 2024 10 29. 14(1): 25878
    Causal role of immune cells in muscle atrophy: mendelian randomization study.
    Xing Yu, Xiaojun Chen, Yunyun Su, Huibin Tang, Liangdi Xie.
      Immune system and inflammation had a great influence on the progression of muscle atrophy. However, the causal relationship with specific immune cell traits remained uncertain. The aim of this study was to elucidate the genetic influences on these associations, providing insights into the underlying mechanisms of muscle atrophy. A bidirectional two-sample Mendelian randomization (MR) analysis was conducted to investigate the causal relationship between immune cell phenotypes and muscle atrophy. Data on immune cell phenotypes were obtained from a research cohort containing data on 731 immune cell phenotypes and data on muscle atrophy were sourced from a Finnish database. MR analysis was performed using the MR-Egger method, weighted median, inverse variance weighting, heterogeneity testing, sensitivity analysis, and multiplicity analysis, with results subjected to false discovery rate(FDR) correction. Additionally, the UK Biobank cohort was utilized as an external validation. A total of 31 immune phenotypes with causal relationships with muscle atrophy were identified, including various phenotypes of conventional dendritic cells, myeloid cells, T cells/B cells/natural killer cells, regulatory cells, and T cell maturation stages. Among them, 12 immune phenotypes were identified as exhibiting a positive causal relationship with muscle atrophy, while 19 immune phenotypes were demonstrated to have a negative causal association, highlighting the complex interactions between immune cells and muscle health. The results of the reverse MR analysis indicated that a negative correlation between muscle atrophy and CD28 on secreting Treg (OR = 0.9038, 95%CI:0.8308 ~ 0.9832, P = 0.0186). A significant positive correlation was revealed by external datasets between the CD25 on IgD + CD38- immune phenotype and the risk of muscle atrophy, which was consistent with the trend observed in the training group (OR = 1.1041, 95% CI: 1.1005-1.1076, P = 0.0263). No evidence of pleiotropy was observed, and the reliability of these findings was demonstrated by the leave-one-out analysis. The findings highlight significant correlations between certain immune cell features and muscle atrophy, providing potential targets for further investigation of immunological mechanisms and therapeutic interventions for this condition.
    Keywords:  GWAS; Genetic analysis; Immune Cell features; Immunology; Mendelian randomization; Muscle atrophy
    DOI:  https://doi.org/10.1038/s41598-024-76828-6
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