bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2024‒07‒14
43 papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Skeletal muscle: molecular structure, myogenesis, biological functions, and diseases.
  2. Tumour-induced alterations in single-nucleus transcriptome of atrophying muscles indicate enhanced protein degradation and reduced oxidative metabolism.
  3. Epigenetic control of skeletal muscle atrophy.
  4. Treadmill running and mechanical overloading improved the strength of the plantaris muscle in the dystrophin-desmin double knockout (DKO) mouse.
  5. Reduced oxidative capacity of skeletal muscle mitochondria is a fundamental consequence of adult ageing.
  6. Skeletal Muscle UCHL1 Negatively Regulates Muscle Development and Recovery after Muscle Injury.
  7. KLF13 restrains Dll4-muscular Notch2 axis to improve the muscle atrophy.
  8. Integrative effects of resistance training and endurance training on mitochondrial remodeling in skeletal muscle.
  9. Physiological Adaptations to Progressive Endurance Exercise Training in Adult and Aged Rats: Insights from the Molecular Transducers of Physical Activity Consortium (MoTrPAC).
  10. Reduced oxidative capacity of skeletal muscle IS NOT an inevitable consequence of adult ageing.
  11. The IRE1α/XBP1 signaling axis drives myoblast fusion in adult skeletal muscle.
  12. Role of TRPC6 in apoptosis of skeletal muscle ischemia/reperfusion injury.
  13. Curcumin-activated Wnt5a pathway mediates Ca2+ channel opening to affect myoblast differentiation and skeletal muscle regeneration.
  14. Dystrophin S3059 phosphorylation partially attenuates denervation atrophy in mouse tibialis anterior muscles.
  15. Fast and slow myofiber nuclei, satellite cells, and size distribution with lifelong endurance exercise in men and women.
  16. Extracellular C1qbp inhibits myogenesis by suppressing NFATc1.
  17. OTUB1 regulates ferroptosis to inhibit myoblast differentiation into myotubes by deubiquitinating P62.
  18. Maintaining mitochondrial NAD+ homeostasis is key for heat-induced skeletal muscle injury prevention despite presence of intracellular cation alterations.
  19. Dual-specificity phosphatases 13 and 27 as key switches in muscle stem cell transition from proliferation to differentiation.
  20. Characterization of Proteome Changes in Aged and Collagen VI-Deficient Human Pericyte Cultures.
  21. PINK1 regulated mitophagy is evident in skeletal muscles.
  22. Sucrose-induced metabolic syndrome differentially affects energy metabolism and fiber phenotype of EDL and soleus muscles during exercise in the rat.
  23. Association of skeletal muscle karyopherin alpha 1 and alpha 2 with myogenesis and insulin action.
  24. Rebuttal: reduced oxidative capacity of skeletal muscle IS NOT an inevitable consequence of adult ageing.
  25. Cancerous Conditions Accelerate the Aging of Skeletal Muscle via Mitochondrial DNA Damage.
  26. Skeletal muscle dysfunction with advancing age.
  27. Deletion of Dux ameliorates muscular dystrophy in mdx mice by attenuating oxidative stress via Nrf2.
  28. SMCHD1 activates the expression of genes required for the expansion of human myoblasts.
  29. Muscle Organoid and Assembloid Systems.
  30. Isolation of Mitochondria from Murine Skeletal Muscle.
  31. Have a little heart (or not): highly minimized skeletal muscle regulatory cassettes with low or no activity in heart.
  32. The role of interleukin-6 family cytokines in cancer cachexia.
  33. Multiparametric identification of putative senescent cells in skeletal muscle via mass cytometry.
  34. High-intensity interval training using electrical stimulation ameliorates muscle fatigue in chronic kidney disease-related cachexia by restoring mitochondrial respiratory dysfunction.
  35. Exercise as a tool to mitigate metabolic disease.
  36. Epsti1 Regulates the Inflammatory Stage of Early Muscle Regeneration through STAT1-VCP Interaction.
  37. Myo-optogenetics: optogenetic stimulation and electrical recording in skeletal muscles.
  38. Effect of mTORC Agonism via MHY1485 with and without Rapamycin on C2C12 Myotube Metabolism.
  39. Striated muscle: an inadequate soil for cancers.
  40. Unveiling the role of circRBBP7 in myoblast proliferation and differentiation: A novel regulator of muscle development.
  41. Marcinek and Ferrucci response to Lanza et al.
  42. Protein biomarker signature in patients with spinal and bulbar muscular atrophy.
  43. Infection and chronic disease activate a systemic brain-muscle signaling axis.
  1. MedComm (2020). 2024 Jul;5(7): e649
    Skeletal muscle: molecular structure, myogenesis, biological functions, and diseases.
    Lan-Ting Feng, Zhi-Nan Chen, Huijie Bian.
      Skeletal muscle is an important motor organ with multinucleated myofibers as its smallest cellular units. Myofibers are formed after undergoing cell differentiation, cell-cell fusion, myonuclei migration, and myofibril crosslinking among other processes and undergo morphological and functional changes or lesions after being stimulated by internal or external factors. The above processes are collectively referred to as myogenesis. After myofibers mature, the function and behavior of skeletal muscle are closely related to the voluntary movement of the body. In this review, we systematically and comprehensively discuss the physiological and pathological processes associated with skeletal muscles from five perspectives: molecule basis, myogenesis, biological function, adaptive changes, and myopathy. In the molecular structure and myogenesis sections, we gave a brief overview, focusing on skeletal muscle-specific fusogens and nuclei-related behaviors including cell-cell fusion and myonuclei localization. Subsequently, we discussed the three biological functions of skeletal muscle (muscle contraction, thermogenesis, and myokines secretion) and its response to stimulation (atrophy, hypertrophy, and regeneration), and finally settled on myopathy. In general, the integration of these contents provides a holistic perspective, which helps to further elucidate the structure, characteristics, and functions of skeletal muscle.
    Keywords:  biological function; myogenesis; myonuclear; myopathy; skeletal muscle
    DOI:  https://doi.org/10.1002/mco2.649
  2. J Cachexia Sarcopenia Muscle. 2024 Jul 13.
    Tumour-induced alterations in single-nucleus transcriptome of atrophying muscles indicate enhanced protein degradation and reduced oxidative metabolism.
    Samet Agca, Aylin Domaniku-Waraich, Sevval Nur Bilgic, Melis Sucuoglu, Meric Dag, Sukru Anil Dogan, Serkan Kir.
      BACKGROUND: Tumour-induced skeletal muscle wasting in the context of cancer cachexia is a condition with profound implications for patient survival. The loss of muscle mass is a significant clinical obstacle and is linked to reduced tolerance to chemotherapy and increased frailty. Understanding the molecular mechanisms driving muscle atrophy is crucial for the design of new therapeutics.METHODS: Lewis lung carcinoma tumours were utilized to induce cachexia and muscle atrophy in mice. Single-nucleus libraries of the tibialis anterior (TA) muscle from tumour-bearing mice and their non-tumour-bearing controls were constructed using 10X Genomics applications following the manufacturer's guidelines. RNA sequencing results were analysed with Cell Ranger software and the Seurat R package. Oxygen consumption of mitochondria isolated from TA muscle was measured using an Oroboros O2k-FluoRespirometer. Mouse primary myotubes were treated with a recombinant ectodysplasin A2 (EDA-A2) protein to activate EDA-A2 receptor (EDA2R) signalling and study changes in gene expression and oxygen consumption.
    RESULTS: Tumour-bearing mice were sacrificed while exhibiting moderate cachexia. Average TA muscle weight was reduced by 11% (P = 0.0207) in these mice. A total of 12 335 nuclei, comprising 6422 nuclei from the control group and 5892 nuclei from atrophying muscles, were studied. The analysis of single-nucleus transcriptomes identified distinct myonuclear gene signatures and a shift towards type IIb myonuclei. Muscle atrophy-related genes, including Atrogin1, MuRF1 and Eda2r, were upregulated in these myonuclei, emphasizing their crucial roles in muscle wasting. Gene set enrichment analysis demonstrated that EDA2R activation and tumour inoculation led to similar expression patterns in muscle cells, including the stimulation of nuclear factor-kappa B, Janus kinase-signal transducer and activator of transcription and transforming growth factor-beta pathways and the suppression of myogenesis and oxidative phosphorylation. Muscle oxidative metabolism was suppressed by both tumours and EDA2R activation.
    CONCLUSIONS: This study identified tumour-induced transcriptional changes in muscle tissue at single-nucleus resolution and highlighted the negative impact of tumours on oxidative metabolism. These findings contribute to a deeper understanding of the molecular mechanisms underlying muscle wasting.
    Keywords:  EDA2R signalling; cancer cachexia; single‐nucleus RNA sequencing; skeletal muscle atrophy
    DOI:  https://doi.org/10.1002/jcsm.13540
  3. Cell Mol Biol Lett. 2024 Jul 08. 29(1): 99
    Epigenetic control of skeletal muscle atrophy.
    Wenpeng Liang, Feng Xu, Li Li, Chunlei Peng, Hualin Sun, Jiaying Qiu, Junjie Sun.
      Skeletal muscular atrophy is a complex disease involving a large number of gene expression regulatory networks and various biological processes. Despite extensive research on this topic, its underlying mechanisms remain elusive, and effective therapeutic approaches are yet to be established. Recent studies have shown that epigenetics play an important role in regulating skeletal muscle atrophy, influencing the expression of numerous genes associated with this condition through the addition or removal of certain chemical modifications at the molecular level. This review article comprehensively summarizes the different types of modifications to DNA, histones, RNA, and their known regulators. We also discuss how epigenetic modifications change during the process of skeletal muscle atrophy, the molecular mechanisms by which epigenetic regulatory proteins control skeletal muscle atrophy, and assess their translational potential. The role of epigenetics on muscle stem cells is also highlighted. In addition, we propose that alternative splicing interacts with epigenetic mechanisms to regulate skeletal muscle mass, offering a novel perspective that enhances our understanding of epigenetic inheritance's role and the regulatory network governing skeletal muscle atrophy. Collectively, advancements in the understanding of epigenetic mechanisms provide invaluable insights into the study of skeletal muscle atrophy. Moreover, this knowledge paves the way for identifying new avenues for the development of more effective therapeutic strategies and pharmaceutical interventions.
    Keywords:  Histone modifications; Skeletal muscle atrophy; Ubiquitin–proteasome; epigenetic; m6A
    DOI:  https://doi.org/10.1186/s11658-024-00618-1
  4. J Physiol. 2024 Jul 09.
    Treadmill running and mechanical overloading improved the strength of the plantaris muscle in the dystrophin-desmin double knockout (DKO) mouse.
    Dylan Moutachi, Janek Hyzewicz, Pauline Roy, Mégane Lemaitre, Damien Bachasson, Helge Amthor, Olli Ritvos, Zhenlin Li, Denis Furling, Onnik Agbulut, Arnaud Ferry.
      Limited knowledge exists regarding the chronic effect of muscular exercise on muscle function in a murine model of severe Duchenne muscular dystrophy (DMD). Here we determined the effects of 1 month of voluntary wheel running (WR), 1 month of enforced treadmill running (TR) and 1 month of mechanical overloading resulting from the removal of the synergic muscles (OVL) in mice lacking both dystrophin and desmin (DKO). Additionally, we examined the effect of activin receptor administration (AR). DKO mice, displaying severe muscle weakness, atrophy and greater susceptibility to contraction-induced functional loss, were exercised or treated with AR at 1 month of age and in situ force production of lower leg muscle was measured at the age of 2 months. We found that TR and OVL increased absolute maximal force and the rate of force development of the plantaris muscle in DKO mice. In contrast, those of the tibialis anterior (TA) muscle remained unaffected by TR and WR. Furthermore, the effects of TR and OVL on plantaris muscle function in DKO mice closely resembled those in mdx mice, a less severe murine DMD model. AR also improved absolute maximal force and the rate of force development of the TA muscle in DKO mice. In conclusion, exercise training improved plantaris muscle weakness in severely affected dystrophic mice. Consequently, these preclinical results may contribute to fostering further investigations aimed at assessing the potential benefits of exercise for DMD patients, particularly resistance training involving a low number of intense muscle contractions. KEY POINTS: Very little is known about the effects of exercise training in a murine model of severe Duchenne muscular dystrophy (DMD). One reason is that it is feared that chronic muscular exercise, particularly that involving intense muscle contractions, could exacerbate the disease. In DKO mice lacking both dystrophin and desmin, characterized by severe lower leg muscle weakness, atrophy and fragility in comparison to the less severe DMD mdx model, we found that enforced treadmill running improved absolute maximal force of the plantaris muscle, while that of tibialis anterior muscle remained unaffected by both enforced treadmill and voluntary wheel running. Furthermore, mechanical overloading, a non-physiological model of chronic resistance exercise, reversed plantaris muscle weakness. Consequently, our findings may have the potential to alleviate concerns and pave the way for exploring the prescription of endurance and resistance training as a viable therapeutic approach for the treatment of dystrophic patients. Additionally, such interventions may serve in mitigating the pathophysiological mechanisms induced by physical inactivity.
    Keywords:  Duchenne muscular dystrophy; chronic muscular exercise; endurance training; maximal force; mice; resistance training
    DOI:  https://doi.org/10.1113/JP286425
  5. J Physiol. 2024 Jul 06.
    Reduced oxidative capacity of skeletal muscle mitochondria is a fundamental consequence of adult ageing.
    David J Marcinek, Luigi Ferrucci.
      
    Keywords:  ageing; magnetic resonance; mitochondria; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1113/JP285040
  6. Int J Mol Sci. 2024 Jul 04. pii: 7330. [Epub ahead of print]25(13):
    Skeletal Muscle UCHL1 Negatively Regulates Muscle Development and Recovery after Muscle Injury.
    Ryan Antony, Katherine Aby, Morgan Montgomery, Yifan Li.
      Ubiquitin C-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme originally found in the brain. Our previous work revealed that UCHL1 was also expressed in skeletal muscle and affected myoblast differentiation and metabolism. In this study, we further tested the role of UCHL1 in myogenesis and muscle regeneration following muscle ischemia-reperfusion (IR) injury. In the C2C12 myoblast, UCHL1 knockdown upregulated MyoD and myogenin and promoted myotube formation. The skeletal muscle-specific knockout (smKO) of UCHL1 increased muscle fiber sizes in young mice (1 to 2 months old) but not in adult mice (3 months old). In IR-injured hindlimb muscle, UCHL1 was upregulated. UCHL1 smKO ameliorated tissue damage and injury-induced inflammation. UCHL1 smKO also upregulated myogenic factors and promoted functional recovery in IR injury muscle. Moreover, UCHL1 smKO increased Akt and Pink1/Parkin activities. The overall results suggest that skeletal muscle UCHL1 is a negative factor in skeletal muscle development and recovery following IR injury and therefore is a potential therapeutic target to improve muscle regeneration and functional recovery following injuries.
    Keywords:  UCHL1; inflammation; ischemia-reperfusion injury; myogenesis; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms25137330
  7. J Cachexia Sarcopenia Muscle. 2024 Jul 08.
    KLF13 restrains Dll4-muscular Notch2 axis to improve the muscle atrophy.
    Shu Yang, Lijiao Xiong, Guangyan Yang, Jiaqing Xiang, Lixing Li, Lin Kang, Zhen Liang.
      BACKGROUND: Muscle atrophy can cause muscle dysfunction and weakness. Krüppel-like factor 13 (KLF13), a central regulator of cellular energy metabolism, is highly expressed in skeletal muscles and implicated in the pathogenesis of several diseases. This study investigated the role of KLF13 in muscle atrophy, which could be a novel therapeutic target.METHODS: The effects of gene knockdown and pharmacological targeting of KLF13 on skeletal muscle atrophy were investigated using cell-based and animal models. Clofoctol, an antibiotic and KLF13 agonist, was also investigated as a candidate for repurposing. The mechanisms related to skeletal muscle atrophy were assessed by measuring the expression levels and activation statuses of key regulatory pathways and validated using gene knockdown and RNA sequencing.
    RESULTS: In a dexamethasone-induced muscle atrophy mouse model, the KLF13 knockout group had decreased muscle strength (N) (1.77 ± 0.10 vs. 1.48 ± 0.16, P < 0.01), muscle weight (%) [gastrocnemius (Gas): 76.0 ± 5.69 vs. 60.7 ± 7.23, P < 0.001; tibialis anterior (TA): 75.8 ± 6.21 vs. 67.5 ± 5.01, P < 0.05], and exhaustive running distance (m) (495.5 ± 64.8 vs. 315.5 ± 60.9, P < 0.05) compared with the control group. KLF13 overexpression preserved muscle mass (Gas: 100 ± 6.38 vs. 120 ± 14.4, P < 0.01) and the exhaustive running distance (423.8 ± 59.04 vs. 530.2 ± 77.45, P < 0.05) in an in vivo diabetes-induced skeletal muscle atrophy model. Clofoctol treatment protected against dexamethasone-induced muscle atrophy. Myotubes treated with dexamethasone, an atrophy-inducing glucocorticoid, were aggravated by KLF13 knockout, but anti-atrophic effects were achieved by inducing KLF13 overexpression. We performed a transcriptome analysis and luciferase reporter assays to further explore this mechanism, finding that delta-like 4 (Dll4) was a novel target gene of KLF13. The KLF13 transcript repressed Dll4, inhibiting the Dll4-Notch2 axis and preventing muscle atrophy. Dexamethasone inhibited KLF13 expression by inhibiting myogenic differentiation 1 (i.e., MYOD1)-mediated KLF13 transcriptional activation and promoting F-Box and WD repeat domain containing 7 (i.e., FBXW7)-mediated KLF13 ubiquitination.
    CONCLUSIONS: This study sheds new light on the mechanisms underlying skeletal muscle atrophy and potential drug targets. KLF13 regulates muscle atrophy and is a potential therapeutic target. Clofoctol is an attractive compound for repurposing studies to treat skeletal muscle atrophy.
    Keywords:  Clofoctol; DLL4; KLF13; Notch; Sarcopenia
    DOI:  https://doi.org/10.1002/jcsm.13538
  8. Eur J Appl Physiol. 2024 Jul 09.
    Integrative effects of resistance training and endurance training on mitochondrial remodeling in skeletal muscle.
    Yong-Cai Zhao, Bing-Hong Gao.
      Resistance training activates mammalian target of rapamycin (mTOR) pathway of hypertrophy for strength gain, while endurance training increases peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) pathway of mitochondrial biogenesis benefiting oxidative phosphorylation. The conventional view suggests that resistance training-induced hypertrophy signaling interferes with endurance training-induced mitochondrial remodeling. However, this idea has been challenged because acute leg press and knee extension in humans enhance both muscle hypertrophy and mitochondrial remodeling signals. Thus, we first examined the muscle mitochondrial remodeling and hypertrophy signals with endurance training and resistance training, respectively. In addition, we discussed the influence of resistance training on muscle mitochondria, demonstrating that the PGC-1α-mediated muscle mitochondrial adaptation and hypertrophy occur simultaneously. The second aim was to discuss the integrative effects of concurrent training, which consists of endurance and resistance training sessions on mitochondrial remodeling. The study found that the resistance training component does not reduce muscle mitochondrial remodeling signals in concurrent training. On the contrary, concurrent training has the potential to amplify skeletal muscle mitochondrial biogenesis compared to a single exercise model. Concurrent training involving differential sequences of resistance and endurance training may result in varied mitochondrial biogenesis signals, which should be linked to the pre-activation of mTOR or PGC-1α signaling. Our review proposed a mechanism for mTOR signaling that promotes PGC-1α signaling through unidentified pathways. This mechanism may be account for the superior muscle mitochondrial remodeling change following the concurrent training. Our review suggested an interaction between resistance training and endurance training in skeletal muscle mitochondrial adaptation.
    Keywords:  Concurrent training; Mitochondrial biogenesis; Skeletal muscle
    DOI:  https://doi.org/10.1007/s00421-024-05549-5
  9. Function (Oxf). 2024 Jul 11. pii: zqae014. [Epub ahead of print]5(4):
    Physiological Adaptations to Progressive Endurance Exercise Training in Adult and Aged Rats: Insights from the Molecular Transducers of Physical Activity Consortium (MoTrPAC).
    MoTrPAC Study Group
      While regular physical activity is a cornerstone of health, wellness, and vitality, the impact of endurance exercise training on molecular signaling within and across tissues remains to be delineated. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to characterize molecular networks underlying the adaptive response to exercise. Here, we describe the endurance exercise training studies undertaken by the Preclinical Animal Sites Studies component of MoTrPAC, in which we sought to develop and implement a standardized endurance exercise protocol in a large cohort of rats. To this end, Adult (6-mo) and Aged (18-mo) female (n = 151) and male (n = 143) Fischer 344 rats were subjected to progressive treadmill training (5 d/wk, ∼70%-75% VO2max) for 1, 2, 4, or 8 wk; sedentary rats were studied as the control group. A total of 18 solid tissues, as well as blood, plasma, and feces, were collected to establish a publicly accessible biorepository and for extensive omics-based analyses by MoTrPAC. Treadmill training was highly effective, with robust improvements in skeletal muscle citrate synthase activity in as little as 1-2 wk and improvements in maximum run speed and maximal oxygen uptake by 4-8 wk. For body mass and composition, notable age- and sex-dependent responses were observed. This work in mature, treadmill-trained rats represents the most comprehensive and publicly accessible tissue biorepository, to date, and provides an unprecedented resource for studying temporal-, sex-, and age-specific responses to endurance exercise training in a preclinical rat model.
    Keywords:  aging; biorepository; body composition; citrate synthase; maximal oxygen uptake; skeletal muscle; training; treadmill
    DOI:  https://doi.org/10.1093/function/zqae014
  10. J Physiol. 2024 Jul 06.
    Reduced oxidative capacity of skeletal muscle IS NOT an inevitable consequence of adult ageing.
    Ian R Lanza, Christopher W Sundberg, Jane A Kent.
      
    Keywords:  ageing; mitochondria; oxidative phosphorylation; skeletal muscle
    DOI:  https://doi.org/10.1113/JP285042
  11. EMBO Rep. 2024 Jul 09.
    The IRE1α/XBP1 signaling axis drives myoblast fusion in adult skeletal muscle.
    Aniket S Joshi, Meiricris Tomaz da Silva, Anirban Roy, Tatiana E Koike, Mingfu Wu, Micah B Castillo, Preethi H Gunaratne, Yu Liu, Takao Iwawaki, Ashok Kumar.
      Skeletal muscle regeneration involves a signaling network that regulates the proliferation, differentiation, and fusion of muscle precursor cells to injured myofibers. IRE1α, one of the arms of the unfolded protein response, regulates cellular proteostasis in response to ER stress. Here, we demonstrate that inducible deletion of IRE1α in satellite cells of mice impairs skeletal muscle regeneration through inhibiting myoblast fusion. Knockdown of IRE1α or its downstream target, X-box protein 1 (XBP1), also inhibits myoblast fusion during myogenesis. Transcriptome analysis revealed that knockdown of IRE1α or XBP1 dysregulates the gene expression of molecules involved in myoblast fusion. The IRE1α-XBP1 axis mediates the gene expression of multiple profusion molecules, including myomaker (Mymk). Spliced XBP1 (sXBP1) transcription factor binds to the promoter of Mymk gene during myogenesis. Overexpression of myomaker in IRE1α-knockdown cultures rescues fusion defects. Inducible deletion of IRE1α in satellite cells also inhibits myoblast fusion and myofiber hypertrophy in response to functional overload. Collectively, our study demonstrates that IRE1α promotes myoblast fusion through sXBP1-mediated up-regulation of the gene expression of multiple profusion molecules, including myomaker.
    Keywords:  IRE1; Muscle Regeneration; Myoblast Fusion; XBP1; and Myomaker
    DOI:  https://doi.org/10.1038/s44319-024-00197-4
  12. Cell Signal. 2024 Jul 04. pii: S0898-6568(24)00257-2. [Epub ahead of print]121 111289
    Role of TRPC6 in apoptosis of skeletal muscle ischemia/reperfusion injury.
    Dong-Ge Xie, Jun-Hao Li, Yun-Long Zhong, Han Han, Jia-Ji Zhang, Zhong-Qing Zhang, Shou-Tian Li.
      BACKGROUND: Skeletal muscle ischaemia-reperfusion injury (IRI) is a prevalent condition encountered in clinical practice, characterised by muscular dystrophy. Owing to limited treatment options and poor prognosis, it can lead to movement impairments, tissue damage, and disability. This study aimed to determine and verify the influence of transient receptor potential canonical 6 (TRPC6) on skeletal muscle IRI, and to explore the role of TRPC6 in the occurrence of skeletal muscle IRI and the signal transduction pathways activated by TRPC6 to provide novel insights for the treatment and intervention of skeletal muscle IRI.METHODS: In vivo ischaemia/reperfusion (I/R) and in vitro hypoxia/reoxygenation (H/R) models were established, and data were comprehensively analysed at histopathological, cellular, and molecular levels, along with the evaluation of the exercise capacity in mice.
    RESULTS: By comparing TRPC6 knockout mice with wild-type mice, we found that TRPC6 knockout of TRPC6 could reduced skeletal muscle injury after I/R or H/R, of skeletal muscle, so as therebyto restoringe some exercise capacity inof mice. TRPC6 knockdown can reduced Ca2+ overload in cells, therebyo reducinge apoptosis. In additionAdditionally, we also found that TRPC6 functionsis not only a key ion channel involved in skeletal muscle I/R injury, but also can affects Ca2+ levels and then phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signalling pathway. by knocking downTherefore, knockdown of TRPC6, so as to alleviated the injury inducedcaused by skeletal muscle I/R or and H/R.
    CONCLUSIONS: These findingsdata indicate that the presence of TRPC6 exacerbatescan aggravate the injury of skeletal muscle injury after I/Rischemia/reperfusion, leading towhich not only causes Ca2+ overload and apoptosis., Additionally, it impairsbut also reduces the self- repair ability of cells by inhibiting the expression of the PI3K/Akt/mTOR signalling pathway. ETo exploringe the function and role of TRPC6 in skeletal muscle maycan presentprovide a novelew approachidea for the treatment of skeletal muscle ischemia/reperfusion injury.
    Keywords:  Akt; Apoptosis; Ca(2+); Ischemia/reperfusion injury; PI3K; Skeletal muscle; TRPC6; mTOR
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111289
  13. J Cachexia Sarcopenia Muscle. 2024 Jul 10.
    Curcumin-activated Wnt5a pathway mediates Ca2+ channel opening to affect myoblast differentiation and skeletal muscle regeneration.
    Mao-Yuan Wang, Jia-Ming Yang, Yi Wu, Hai Li, Yan-Biao Zhong, Yun Luo, Rui-Lian Xie.
      BACKGROUND: Skeletal muscle injury is one of the most common sports injuries; if not properly treated or not effective rehabilitation treatment after injury, it can be transformed into chronic cumulative injury. Curcumin, an herbal ingredient, has been found to promote skeletal muscle injury repair and regeneration. The Wnt5a pathway is related to the expression of myogenic regulatory factors, and Ca2+ promotes the differentiation and fusion process of myoblasts. This study explored the effect and mechanism of curcumin on myoblast differentiation during the repair and regeneration of injured skeletal muscle and its relationship with the Wnt5a pathway and Ca2+ channel.METHODS: Myogenic differentiation of C2C12 cells was induced with 2% horse serum, and a mouse (male, 10 weeks old) model of acute skeletal muscle injury was established using cardiotoxin (20 μL). In addition, we constructed a Wnt5a knockdown C2C12 cell model and a Wnt5a knockout mouse model. Besides, curcumin was added to the cell culture solution (80 mg/L) and fed to the mice (50 mg/kg). Fluorescence microscopy was used to determine the concentration of Ca2+. Western blot and RT-qPCR were used to detect the protein and mRNA levels of Wnt5a, CaN, NFAT2, MyoD, Myf5, Pax7, and Myogenin. The expression levels of MyoD, Myf5, Myogenin, MHC, Desmin, and NFAT2 were detected using immunofluorescence techniques. In addition, MyoD expression was observed using immunohistochemistry, and morphological changes in mouse muscle tissue were observed using HE staining.
    RESULTS: During myoblast differentiation and muscle regeneration, Wnt5a expression was upregulated (P < 0.001) and the Wnt5a signalling pathway was activated. Wnt5a overexpression promoted the expression of MyoD, Myf5, Myogenin, MHC, and Desmin (P < 0.05), and conversely, knockdown of Wnt5a inhibited their expression (P < 0.001). The Wnt5a pathway mediated the opening of Ca2+ channels, regulated the expression levels of CaN, NFAT2, MyoD, Myf5, Myogenin, MHC, and Desmin (P < 0.01) and promoted the differentiation of C2C12 myoblasts and the repair and regeneration of injured skeletal muscle. The expression of Wnt5a, CaN, NFAT2, MyoD, Myogenin, Myf5, and MHC in C2C12 myoblast was significantly increased after curcumin intervention (P < 0.05); however, their expression decreased significantly after knocking down Wnt5a on the basis of curcumin intervention (P < 0.05). Similarly, in Wnt5a knockout mice, the promotion of muscle regeneration by curcumin was significantly attenuated.
    CONCLUSIONS: Curcumin can activate the Wnt5a signalling pathway and mediate the opening of Ca2+ channels to accelerate the myogenic differentiation of C2C12 cells and the repair and regeneration of injured skeletal muscle.
    Keywords:  Ca2+; Curcumin; Muscle regeneration; Myoblast differentiation; Wnt5a
    DOI:  https://doi.org/10.1002/jcsm.13535
  14. Physiol Rep. 2024 Jul;12(13): e16145
    Dystrophin S3059 phosphorylation partially attenuates denervation atrophy in mouse tibialis anterior muscles.
    Kristy Swiderski, Timur Naim, Jennifer Trieu, Annabel Chee, Marco J Herold, Andrew J Kueh, Craig A Goodman, Paul Gregorevic, Gordon S Lynch.
      The dystrophin protein has well-characterized roles in force transmission and maintaining membrane integrity during muscle contraction. Studies have reported decreased expression of dystrophin in atrophying muscles during wasting conditions, and that restoration of dystrophin can attenuate atrophy, suggesting a role in maintaining muscle mass. Phosphorylation of S3059 within the cysteine-rich region of dystrophin enhances binding between dystrophin and β-dystroglycan, and mimicking phosphorylation at this site by site-directed mutagenesis attenuates myotube atrophy in vitro. To determine whether dystrophin phosphorylation can attenuate muscle wasting in vivo, CRISPR-Cas9 was used to generate mice with whole body mutations of S3059 to either alanine (DmdS3059A) or glutamate (DmdS3059E), to mimic a loss of, or constitutive phosphorylation of S3059, on all endogenous dystrophin isoforms, respectively. Sciatic nerve transection was performed on these mice to determine whether phosphorylation of dystrophin S3059 could attenuate denervation atrophy. At 14 days post denervation, atrophy of tibialis anterior (TA) but not gastrocnemius or soleus muscles, was partially attenuated in DmdS3059E mice relative to WT mice. Attenuation of atrophy was associated with increased expression of β-dystroglycan in TA muscles of DmdS3059E mice. Dystrophin S3059 phosphorylation can partially attenuate denervation-induced atrophy, but may have more significant impact in less severe modes of muscle wasting.
    Keywords:  S3059; denervation; dystrophin; muscle atrophy; phosphorylation
    DOI:  https://doi.org/10.14814/phy2.16145
  15. Physiol Rep. 2024 Jul;12(13): e16052
    Fast and slow myofiber nuclei, satellite cells, and size distribution with lifelong endurance exercise in men and women.
    Cristhian F Montenegro, Chad Skiles, Dillon J Kuszmaul, Aaron Gouw, Kiril Minchev, Toby L Chambers, Ulrika Raue, Todd A Trappe, Scott Trappe.
      We previously observed lifelong endurance exercise (LLE) influenced quadriceps whole-muscle and myofiber size in a fiber-type and sex-specific manner. The current follow-up exploratory investigation examined myofiber size regulators and myofiber size distribution in vastus lateralis biopsies from these same LLE men (n = 21, 74 ± 1 years) and women (n = 7, 72 ± 2 years) as well as old, healthy nonexercisers (OH; men: n = 10, 75 ± 1 years; women: n = 10, 75 ± 1 years) and young exercisers (YE; men: n = 10, 25 ± 1 years; women: n = 10, 25 ± 1 years). LLE exercised ~5 days/week, ~7 h/week for the previous 52 ± 1 years. Slow (myosin heavy chain (MHC) I) and fast (MHC IIa) myofiber nuclei/fiber, myonuclear domain, satellite cells/fiber, and satellite cell density were not influenced (p > 0.05) by LLE in men and women. The aging groups had ~50%-60% higher proportion of large (>7000 μm2) and small (<3000 μm2) myofibers (OH; men: 44%, women: 48%, LLE; men: 42%, women: 42%, YE; men: 27%, women: 29%). LLE men had triple the proportion of large slow fibers (LLE: 21%, YE: 7%, OH: 7%), while LLE women had more small slow fibers (LLE: 15%, YE: 8%, OH: 9%). LLE reduced by ~50% the proportion of small fast (MHC II containing) fibers in the aging men (OH: 14%, LLE: 7%) and women (OH: 35%, LLE: 18%). These data, coupled with previous findings, suggest that myonuclei and satellite cell content are uninfluenced by lifelong endurance exercise in men ~60-90 years, and this now also extends to septuagenarian lifelong endurance exercise women. Additionally, lifelong endurance exercise appears to influence the relative abundance of small and large myofibers (fast and slow) differently between men and women.
    Keywords:  aging; cross‐sectional area; fiber type specific; masters athletes; myonuclei; satellite cells
    DOI:  https://doi.org/10.14814/phy2.16052
  16. Sci Rep. 2024 Jul 08. 14(1): 15678
    Extracellular C1qbp inhibits myogenesis by suppressing NFATc1.
    Jin-Man Kim, Ho Kyoung Kim, Han Jin Cho, Sung-Ah Moon, Yewon Kim, Jeong Yeon Hong, Seung Hun Lee, Kyunggon Kim, Jung-Min Koh.
      Aging and lack of exercise are the most important etiological factors for muscle loss. We hypothesized that new factors that contribute to muscle loss could be identified from ones commonly altered in expression in aged and exercise-limited skeletal muscles. Mouse gastrocnemius muscles were subjected to mass spectrometry-based proteomic analysis. The muscle proteomes of hindlimb-unloaded and aged mice were compared to those of exercised and young mice, respectively. C1qbp expression was significantly upregulated in the muscles of both hindlimb-unloaded and aged mice. In vitro myogenic differentiation was not affected by altering intracellular C1qbp expression but was significantly suppressed upon recombinant C1qbp treatment. Additionally, recombinant C1qbp repressed the protein level but not the mRNA level of NFATc1. NFATc1 recruited the transcriptional coactivator p300, leading to the upregulation of acetylated histone H3 levels. Furthermore, NFATc1 silencing inhibited p300 recruitment, downregulated acetylated histone H3 levels, and consequently suppressed myogenic differentiation. The expression of C1qbp was inversely correlated with that of NFATc1 in the gastrocnemius muscles of exercised or hindlimb-unloaded, and young or aged mice. These findings demonstrate a novel role of extracellular C1qbp in suppressing myogenesis by inhibiting the NFATc1/p300 complex. Thus, C1qbp can serve as a novel therapeutic target for muscle loss.
    Keywords:  C1qbp; Exercise; Hindlimb unloading; Myogenesis; NFATc1; p300
    DOI:  https://doi.org/10.1038/s41598-024-66549-1
  17. Sci Rep. 2024 Jul 08. 14(1): 15696
    OTUB1 regulates ferroptosis to inhibit myoblast differentiation into myotubes by deubiquitinating P62.
    Limin Wei, Yanhong Li, Helin Tan, Yue Peng, Qian Liu, Tingting Zheng, Feng Li, Zhongxian Xu.
      As the largest organ in the human body, skeletal muscle is essential for breathing support, movement initiation, and maintenance homeostasis. It has been shown that programmed cell death (PCD), which includes autophagy, apoptosis, and necrosis, is essential for the development of skeletal muscle. A novel form of PCD called ferroptosis is still poorly understood in relation to skeletal muscle. In this study, we observed that the activation of ferroptosis significantly impeded the differentiation of C2C12 myoblasts into myotubes and concurrently suppressed the expression of OTUB1, a crucial deubiquitinating enzyme. OTUB1-silenced C2C12 mouse myoblasts were used to investigate the function of OTUB1 in ferroptosis. The results show that OTUB1 knockdown in vitro significantly increased C2C12 ferroptosis and inhibited myogenesis. Interestingly, the induction of ferroptosis resulting from OTUB1 knockdown was concomitant with the activation of autophagy. Furthermore, OTUB1 interacted with the P62 protein and stabilized its expression by deubiquitinating it, thereby inhibiting autophagy-dependent ferroptosis and promoting myogenesis. All of these findings demonstrate the critical role that OTUB1 plays in controlling ferroptosis, and we suggest that focusing on the OTUB1-P62 axis may be a useful tactic in the treatment and prevention of disorders involving the skeletal muscle.
    Keywords:  Autophagy; Ferroptosis; Myogenesis; OTUB1; Skeletal muscle
    DOI:  https://doi.org/10.1038/s41598-024-66868-3
  18. Appl Physiol Nutr Metab. 2024 Jul 09.
    Maintaining mitochondrial NAD+ homeostasis is key for heat-induced skeletal muscle injury prevention despite presence of intracellular cation alterations.
    Yifan Chen, Tianzheng Yu, Patricia Deuster.
      Mitochondrial dysfunction is implicated in heat-induced skeletal muscle injury and its underlying mechanisms remain unclear. Evidence suggests that cellular ions and molecules, including divalent cations and adenine nucleotides, are involved in the regulation of mitochondrial function. In this study, we examined Ca2+, Mg2+, and NAD+ levels in mouse C2C12 myoblasts and skeletal muscle in response to heat exposure. During heat exposure, mitochondrial Ca2+ levels increased significantly, whereas cytosolic C2+ levels remained unaltered. The mitochondrial Ca2+ levels in the skeletal muscle of heat-exposed mice were 28% higher, compared to control mice. No changes in cytosolic Ca2+ were detected between the two groups. Following heat exposure, cytosolic and mitochondrial Mg2+ levels were reduced by 47% and 23% in C2C12 myoblasts, and by 51% and 44% in mouse skeletal muscles, respectively. In addition, heat exposure decreased mitochondrial NAD+ levels by 32% and 26% in C2C12 myoblasts and mouse skeletal muscles, respectively. Treatment with the NAD+ precursor nicotinamide riboside (NR) partially prevented heat-induced depletion of NAD+. Additionally, NR significantly reduced heat-increased mitochondrial fission, mitochondrial depolarization, and apoptosis in C2C12 myoblasts and mouse skeletal muscles. No effects of NR on heat-induced changes in intracellular Ca2+ and Mg2+ levels were observed. This study provides the in vitro and in vivo evidence that acute heat stress causes alterations in mitochondrial Ca2+, Mg2+, and NAD+ homeostasis. Our results suggest mitochondrial NAD+> homeostasis as a therapeutic target for the prevention of heat-induced skeletal muscle injury.
    DOI:  https://doi.org/10.1139/apnm-2024-0157
  19. Stem Cells. 2024 Jul 08. pii: sxae045. [Epub ahead of print]
    Dual-specificity phosphatases 13 and 27 as key switches in muscle stem cell transition from proliferation to differentiation.
    Takuto Hayashi, Shunya Sadaki, Ryosuke Tsuji, Risa Okada, Sayaka Fuseya, Maho Kanai, Ayano Nakamura, Yui Okamura, Masafumi Muratani, Gu Wenchao, Takehito Sugasawa, Seiya Mizuno, Eiji Warabi, Takashi Kudo, Satoru Takahashi, Ryo Fujita.
      Muscle regeneration depends on muscle stem cell (MuSC) activity. Myogenic regulatory factors, including myoblast determination protein 1 (MyoD), regulate the fate transition of MuSCs. However, the direct target of MYOD in the process is not completely clear. Using previously established MyoD knock-in (MyoD-KI) mice, we revealed that MyoD targets dual-specificity phosphatase (Dusp) 13 and Dusp27. In Dusp13:Dusp27 double knock-out (DKO) mice, the ability for muscle regeneration after injury was reduced. Moreover, single-cell RNA sequencing of MyoD-high expressing MuSCs from MyoD-KI mice revealed that Dusp13 and Dusp27 are expressed only in specific populations within MyoD-high MuSCs, which also express Myogenin. Overexpressing Dusp13 in MuSCs causes premature muscle differentiation. Thus, we propose a model where DUSP13 and DUSP27 contribute to the fate transition of MuSCs from proliferation to differentiation during myogenesis.
    Keywords:  Dual specificity phosphatase 13:27; Muscle stem cell; MyoD; Regeneration; Single-cell RNA-sequencing
    DOI:  https://doi.org/10.1093/stmcls/sxae045
  20. Int J Mol Sci. 2024 Jun 28. pii: 7118. [Epub ahead of print]25(13):
    Characterization of Proteome Changes in Aged and Collagen VI-Deficient Human Pericyte Cultures.
    Manuela Moriggi, Enrica Torretta, Matilde Cescon, Loris Russo, Ilaria Gregorio, Paola Braghetta, Patrizia Sabatelli, Cesare Faldini, Luciano Merlini, Cesare Gargioli, Paolo Bonaldo, Cecilia Gelfi, Daniele Capitanio.
      Pericytes are a distinct type of cells interacting with endothelial cells in blood vessels and contributing to endothelial barrier integrity. Furthermore, pericytes show mesenchymal stem cell properties. Muscle-derived pericytes can demonstrate both angiogenic and myogenic capabilities. It is well known that regenerative abilities and muscle stem cell potential decline during aging, leading to sarcopenia. Therefore, this study aimed to investigate the potential of pericytes in supporting muscle differentiation and angiogenesis in elderly individuals and in patients affected by Ullrich congenital muscular dystrophy or by Bethlem myopathy, two inherited conditions caused by mutations in collagen VI genes and sharing similarities with the progressive skeletal muscle changes observed during aging. The study characterized pericytes from different age groups and from individuals with collagen VI deficiency by mass spectrometry-based proteomic and bioinformatic analyses. The findings revealed that aged pericytes display metabolic changes comparable to those seen in aging skeletal muscle, as well as a decline in their stem potential, reduced protein synthesis, and alterations in focal adhesion and contractility, pointing to a decrease in their ability to form blood vessels. Strikingly, pericytes from young patients with collagen VI deficiency showed similar characteristics to aged pericytes, but were found to still handle oxidative stress effectively together with an enhanced angiogenic capacity.
    Keywords:  Bethlem myopathy; Ullrich congenital muscular dystrophy; muscle aging; myogenic differentiation; pericyte; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms25137118
  21. Autophagy Rep. 2024 Mar 11. 3(1): 2326402
    PINK1 regulated mitophagy is evident in skeletal muscles.
    Francois Singh, Lea Wilhelm, Alan R Prescott, Kevin Ostacolo, Jin-Feng Zhao, Margret H Ogmundsdottir, Ian G Ganley.
      PINK1, mutated in familial forms of Parkinson's disease, initiates mitophagy following mitochondrial depolarization. However, it is difficult to monitor this pathway physiologically in mice as loss of PINK1 does not alter basal mitophagy levels in most tissues. To further characterize this pathway in vivo, we used mito-QC mice in which loss of PINK1 was combined with the mitochondrial-associated POLGD257A mutation. We focused on skeletal muscle as gene expression data indicates that this tissue has the highest PINK1 levels. We found that loss of PINK1 in oxidative hindlimb muscle significantly reduced mitophagy. Of interest, the presence of the POLGD257A mutation, while having a minor effect in most tissues, restored levels of muscle mitophagy caused by the loss of PINK1. Although our observations highlight that multiple mitophagy pathways operate within a single tissue, we identify skeletal muscle as a tissue of choice for the study of PINK1-dependant mitophagy under basal conditions.
    Keywords:  PINK1; POLG; Parkinson’s; mitophagy; muscle; mutator
    DOI:  https://doi.org/10.1080/27694127.2024.2326402
  22. Physiol Rep. 2024 Jul;12(13): e16126
    Sucrose-induced metabolic syndrome differentially affects energy metabolism and fiber phenotype of EDL and soleus muscles during exercise in the rat.
    Rodríguez-Correa Eduardo, Carvajal Karla.
      Molecular mechanisms associated to improvement of metabolic syndrome (MetS) during exercise are not fully elucidated. MetS was induced in 250 g male Wistar rats by 30% sucrose in drinking water. Control rats receiving tap water were controls, both groups received solid standard diet. After 14 weeks, an endurance exercised group, and a sedentary were formed for 8 weeks. The soleus and extensor digitorum longus (EDL) muscles were dissected to determine contractile performance, expression of myosin heavy chain isoforms, PGC1α, AMPKα2, NFATC1, MEF2a, SIX1, EYA1, FOXO1, key metabolic enzymes activities. Exercise mildly improved MetS features. MetS didn't alter the contractile performance of the muscles. Exercise didn't altered expression of PGC1α, NFATC1, SIX1 and EYA1 on MetS EDL whereas NFATC1 increased in soleus. Only citrate synthase was affected by MetS on the EDL and this was partially reverted by exercise. Soleus α-ketoglutarate dehydrogenase activity was increased by exercise but MetS rendered the muscle resistant to this effect. MetS affects mostly the EDL muscle, and endurance exercise only partially reverts this. Soleus muscle seems more resilient to MetS. We highlight the importance of studying both muscles during MetS, and their metabolic remodeling on the development and treatment of MetS by exercise.
    Keywords:  exercise; metabolic syndrome; metabolism; myosin; skeletal muscle
    DOI:  https://doi.org/10.14814/phy2.16126
  23. Pol Arch Intern Med. 2024 Jul 08. pii: 16797. [Epub ahead of print]
    Association of skeletal muscle karyopherin alpha 1 and alpha 2 with myogenesis and insulin action.
    Monika Karczewska-Kupczewska, Magdalena Stefanowicz, Agnieszka Nikołajuk, Marek Strączkowski.
      
    DOI:  https://doi.org/10.20452/pamw.16797
  24. J Physiol. 2024 Jul 06.
    Rebuttal: reduced oxidative capacity of skeletal muscle IS NOT an inevitable consequence of adult ageing.
    Ian R Lanza, Christopher W Sundberg, Jane A Kent.
      
    Keywords:  ageing; mitochondria; muscle; oxidative phosphorylation
    DOI:  https://doi.org/10.1113/JP286695
  25. Int J Mol Sci. 2024 Jun 27. pii: 7060. [Epub ahead of print]25(13):
    Cancerous Conditions Accelerate the Aging of Skeletal Muscle via Mitochondrial DNA Damage.
    Yi Luo, Rina Fujiwara-Tani, Isao Kawahara, Kei Goto, Shota Nukaga, Ryoichi Nishida, Chie Nakashima, Takamitsu Sasaki, Yoshihiro Miyagawa, Ruiko Ogata, Kiyomu Fujii, Hitoshi Ohmori, Hiroki Kuniyasu.
      Skeletal muscle aging and sarcopenia result in similar changes in the levels of aging markers. However, few studies have examined cancer sarcopenia from the perspective of aging. Therefore, this study investigated aging in cancer sarcopenia and explored its causes in vitro and in vivo. In mouse aging, in vitro cachexia, and mouse cachexia models, skeletal muscles showed similar changes in aging markers including oxidative stress, fibrosis, reduced muscle differentiation potential, and telomere shortening. Furthermore, examination of mitochondrial DNA from skeletal muscle revealed a 5 kb deletion in the major arc; truncation of complexes I, IV, and V in the electron transport chain; and reduced oxidative phosphorylation (OXPHOS). The mouse cachexia model demonstrated high levels of high-mobility group box-1 (HMGB1) and tumor necrosis factor-α (TNFα) in cancer ascites. Continuous administration of neutralizing antibodies against HMGB1 and TNFα in this model reduced oxidative stress and abrogated mitochondrial DNA deletion. These results suggest that in cancer sarcopenia, mitochondrial oxidative stress caused by inflammatory cytokines leads to mitochondrial DNA damage, which in turn leads to decreased OXPHOS and the promotion of aging.
    Keywords:  aging; cancer sarcopenia; mitochondria; mitochondrial DNA
    DOI:  https://doi.org/10.3390/ijms25137060
  26. Clin Sci (Lond). 2024 Jul 17. 138(14): 863-882
    Skeletal muscle dysfunction with advancing age.
    Pardeep Pabla, Eleanor J Jones, Mathew Piasecki, Bethan E Phillips.
      As a result of advances in medical treatments and associated policy over the last century, life expectancy has risen substantially and continues to increase globally. However, the disconnect between lifespan and 'health span' (the length of time spent in a healthy, disease-free state) has also increased, with skeletal muscle being a substantial contributor to this. Biological ageing is accompanied by declines in both skeletal muscle mass and function, termed sarcopenia. The mechanisms underpinning sarcopenia are multifactorial and are known to include marked alterations in muscle protein turnover and adaptations to the neural input to muscle. However, to date, the relative contribution of each factor remains largely unexplored. Specifically, muscle protein synthetic responses to key anabolic stimuli are blunted with advancing age, whilst alterations to neural components, spanning from the motor cortex and motoneuron excitability to the neuromuscular junction, may explain the greater magnitude of function losses when compared with mass. The consequences of these losses can be devastating for individuals, their support networks, and healthcare services; with clear detrimental impacts on both clinical (e.g., mortality, frailty, and post-treatment complications) and societal (e.g., independence maintenance) outcomes. Whether declines in muscle quantity and quality are an inevitable component of ageing remains to be completely understood. Nevertheless, strategies to mitigate these declines are of vital importance to improve the health span of older adults. This review aims to provide an overview of the declines in skeletal muscle mass and function with advancing age, describes the wide-ranging implications of these declines, and finally suggests strategies to mitigate them, including the merits of emerging pharmaceutical agents.
    Keywords:  activity; aging; neuromuscular; physical function; skeletal muscle
    DOI:  https://doi.org/10.1042/CS20231197
  27. FASEB J. 2024 Jul 31. 38(14): e23771
    Deletion of Dux ameliorates muscular dystrophy in mdx mice by attenuating oxidative stress via Nrf2.
    Siyuan Sun, Wen Zhai, Ruixue Zhang, Na Cai.
      DUX4 has been widely reported in facioscapulohumeral muscular dystrophy, but its role in Duchenne muscular dystrophy (DMD) is unclear. Dux is the mouse paralog of DUX4. In Dux-/- mdx mice, forelimb grip strength test and treadmill test were performed, and extensor digitorum longus (EDL) contraction properties were measured to assess skeletal muscle function. Pathological changes in mice were determined by serum CK and LDH levels and muscle Masson staining. Inflammatory factors, oxidative stress, and mitochondrial function indicators were detected using kits. Primary muscle satellite cells were isolated, and the antioxidant molecule Nrf2 was detected. MTT assay and Edu assay were used to evaluate proliferation and TUNEL assay for cell death. The results show that the deletion of Dux enhanced forelimb grip strength and EDL contractility, prolonged running time and distance in mdx mice. Deleting Dux also attenuated muscle fibrosis, inflammation, oxidative stress, and mitochondrial dysfunction in mdx mice. Furthermore, Dux deficiency promoted proliferation and survival of muscle satellite cells by increasing Nrf2 levels in mdx mice.
    Keywords:  DUX4; Nrf2; muscle satellite cell; muscular dystrophy; oxidative stress
    DOI:  https://doi.org/10.1096/fj.202400195R
  28. Nucleic Acids Res. 2024 Jul 12. pii: gkae600. [Epub ahead of print]
    SMCHD1 activates the expression of genes required for the expansion of human myoblasts.
    Matthew Man-Kin Wong, Sarah Hachmer, Ed Gardner, Valeria Runfola, Eric Arezza, Lynn A Megeney, Charles P Emerson, Davide Gabellini, F Jeffrey Dilworth.
      SMCHD1 is an epigenetic regulatory protein known to modulate the targeted repression of large chromatin domains. Diminished SMCHD1 function in muscle fibers causes Facioscapulohumeral Muscular Dystrophy (FSHD2) through derepression of the D4Z4 chromatin domain, an event which permits the aberrant expression of the disease-causing gene DUX4. Given that SMCHD1 plays a broader role in establishing the cellular epigenome, we examined whether loss of SMCHD1 function might affect muscle homeostasis through additional mechanisms. Here we show that acute depletion of SMCHD1 results in a DUX4-independent defect in myoblast proliferation. Genomic and transcriptomic experiments determined that SMCHD1 associates with enhancers of genes controlling cell cycle to activate their expression. Amongst these cell cycle regulatory genes, we identified LAP2 as a key target of SMCHD1 required for the expansion of myoblasts, where the ectopic expression of LAP2 rescues the proliferation defect of SMCHD1-depleted cells. Thus, the epigenetic regulator SMCHD1 can play the role of a transcriptional co-activator for maintaining the expression of genes required for muscle progenitor expansion. This DUX4-independent role for SMCHD1 in myoblasts suggests that the pathology of FSHD2 may be a consequence of defective muscle regeneration in addition to the muscle wasting caused by spurious DUX4 expression.
    DOI:  https://doi.org/10.1093/nar/gkae600
  29. Adv Exp Med Biol. 2024 Jul 10.
    Muscle Organoid and Assembloid Systems.
    Hazar Eren Soydan, Ayşegül Doğan.
      Skeletal muscle is one of the most complex and largest tissues that perform important processes in the body, including performing voluntary movements and maintaining body temperature. Disruption of muscle homeostasis results in the development of several disorders, including diabetes and sarcopenia. To study the developmental and regenerative dynamics of skeletal muscle and the mechanism behind muscle diseases, it is important to model skeletal muscle and diseases in vitro. Since skeletal muscle has a complex structure and interaction with other tissues and cells that are required to perform their function, conventional 2D cultures are not sufficient to model the skeletal muscle with their interactions. Advances in the field of organoids and assembloids will enable the establishment of more complex and realistic tissue or disease models which cannot be fully recapitulated in conventional 2D culture systems for use in several areas, including disease research, regenerative, and tissue biology. To overcome these limitations, 3D organoid systems and assembloid systems are promising because of their success in recapitulating the complex structural organization, function, and cellular interactions of skeletal muscle.
    Keywords:  Muscle assembloids; Muscle organoid; Muscle tissue; Three-dimensional culture
    DOI:  https://doi.org/10.1007/5584_2024_816
  30. Methods Mol Biol. 2024 ;2816 77-85
    Isolation of Mitochondria from Murine Skeletal Muscle.
    Li Dong, Xuejun Li, Ang Li, Jianxun Yi, Jingsong Zhou.
      Skeletal muscle is one of the largest tissues in human body. Besides enabling voluntary movements and maintaining body's metabolic homeostasis, skeletal muscle is also a target of many pathological conditions. Mitochondria occupy 10-15% volume of a muscle myofiber and regulate many cellular processes, which often determine the fate of the cell. Isolation of mitochondria from skeletal muscle provides opportunities for various multi-omics studies with a focus on mitochondria in biomedical research field. Here we describe a protocol to efficiently isolate mitochondria with high quality and purity from skeletal muscle of mice using Nycodenz density gradient ultracentrifugation.
    Keywords:  Mitochondria isolation; Nycodenz density gradient ultracentrifugation; Skeletal muscle
    DOI:  https://doi.org/10.1007/978-1-0716-3902-3_8
  31. Hum Gene Ther. 2024 Jul 06.
    Have a little heart (or not): highly minimized skeletal muscle regulatory cassettes with low or no activity in heart.
    Charis Himeda, Takako I Jones, Peter L Jones.
      Adeno-associated virus (AAV)-mediated gene therapies for certain muscle disorders require regulatory cassettes that provide high-level, striated muscle-specific activity. However, cardiotoxicity has emerged as a serious concern in clinical trials for Duchenne muscular dystrophy and X-linked myotubular myopathy. While this may be caused by systemic inflammatory effects of the treatment, high transgene expression in the heart may also play a role. Thus, certain muscle disorders may require a modulated level of therapeutic expression in the heart, while others may not require any cardiac expression at all. Additionally, the size of some cargos requires regulatory cassettes to be small enough that large cDNAs and other therapeutic payloads can be accommodated. Thus, we have performed enhancer/promoter optimization to develop highly minimized regulatory cassettes that are active in skeletal muscles, with either low or no detectable activity in cardiac muscle. Our no-heart (NH) cassette is active in most skeletal muscles, but exhibits only very low activity in extensor digitorum longus (EDL), soleus, and diaphragm, and no activity in heart. By contrast, our have-a-little-heart (HLH) cassette displays high activity in most skeletal muscles, comparable to the ~800-bp CK8 cassette, with increased activity in EDL, soleus, and diaphragm, and low activity in heart. Due to their small size, these cassettes can be used in therapeutic strategies with both flexible (e.g., antisense) and stringent (e.g., CRISPR/Cas or bicistronic) size limitations. Thus, our new cassettes may be useful for gene therapies of muscle disorders in which the need for low or almost no expression in cardiac muscle would outweigh the need for high levels of therapeutic product in certain skeletal muscles.
    DOI:  https://doi.org/10.1089/hum.2024.041
  32. FEBS J. 2024 Jul 08.
    The role of interleukin-6 family cytokines in cancer cachexia.
    Samet Agca, Serkan Kir.
      Cachexia is a wasting syndrome that manifests in more than half of all cancer patients. Cancer-associated cachexia negatively influences the survival of patients and their quality of life. It is characterized by a rapid loss of adipose and skeletal muscle tissues, which is partly mediated by inflammatory cytokines. Here, we explored the crucial roles of interleukin-6 (IL-6) family cytokines, including IL-6, leukemia inhibitory factor, and oncostatin M, in the development of cancer cachexia. These cytokines have been shown to exacerbate cachexia by promoting the wasting of adipose and muscle tissues, activating mechanisms that enhance lipolysis and proteolysis. Overlapping effects of the IL-6 family cytokines depend on janus kinase/signal transducer and activator of transcription 3 signaling. We argue that the blockade of these cytokine pathways individually may fail due to redundancy and future therapeutic approaches should target common downstream elements to yield effective clinical outcomes.
    Keywords:  adipose tissue wasting; cancer cachexia; interleukin‐6; leukemia inhibitory factor; muscle atrophy; oncostatin M
    DOI:  https://doi.org/10.1111/febs.17224
  33. Cytometry A. 2024 Jul 12.
    Multiparametric identification of putative senescent cells in skeletal muscle via mass cytometry.
    Yijia Li, Nameera Baig, Daniel Roncancio, Kris Elbein, Dawn Lowe, Michael Kyba, Edgar A Arriaga.
      Senescence is an irreversible arrest of the cell cycle that can be characterized by markers of senescence such as p16, p21, and KI-67. The characterization of different senescence-associated phenotypes requires selection of the most relevant senescence markers to define reliable cytometric methodologies. Mass cytometry (a.k.a. Cytometry by time of flight, CyTOF) can monitor up to 40 different cell markers at the single-cell level and has the potential to integrate multiple senescence and other phenotypic markers to identify senescent cells within a complex tissue such as skeletal muscle, with greater accuracy and scalability than traditional bulk measurements and flow cytometry-based measurements. This article introduces an analysis framework for detecting putative senescent cells based on clustering, outlier detection, and Boolean logic for outliers. Results show that the pipeline can identify putative senescent cells in skeletal muscle with well-established markers such as p21 and potential markers such as GAPDH. It was also found that heterogeneity of putative senescent cells in skeletal muscle can partly be explained by their cell type. Additionally, autophagy-related proteins ATG4A, LRRK2, and GLB1 were identified as important proteins in predicting the putative senescent population, providing insights into the association between autophagy and senescence. It was observed that sex did not affect the proportion of putative senescent cells among total cells. However, age did have an effect, with a higher proportion observed in fibro/adipogenic progenitors (FAPs), satellite cells, M1 and M2 macrophages from old mice. Moreover, putative senescent cells from muscle of old and young mice show different expression levels of senescence-related proteins, with putative senescent cells of old mice having higher levels of p21 and GAPDH, whereas putative senescent cells of young mice had higher levels of IL-6. Overall, the analysis framework prioritizes multiple senescence-associated proteins to characterize putative senescent cells sourced from tissue made of different cell types.
    Keywords:  aging; autophagy; clustering; erythro‐myeloid progenitors; fibro/adipogenic progenitors; macrophages; mass cytometry; outlier detection; satellite cells; senescence; skeletal muscle
    DOI:  https://doi.org/10.1002/cyto.a.24853
  34. Front Physiol. 2024 ;15 1423504
    High-intensity interval training using electrical stimulation ameliorates muscle fatigue in chronic kidney disease-related cachexia by restoring mitochondrial respiratory dysfunction.
    Hiroyori Fusagawa, Tatsuya Sato, Takashi Yamada, Azuma Naito, Nao Tokuda, Nao Yamauchi, Nobutoshi Ichise, Toshifumi Ogawa, Takuro Karaushi, Atsushi Teramoto, Noritsugu Tohse.
      Background: Exercise, especially high-intensity interval training (HIIT), can increase mitochondrial respiratory capacity and enhance muscular endurance, but its systemic burden makes it difficult to safely and continuously prescribe for patients with chronic kidney disease (CKD)-related cachexia who are in poor general condition. In this study, we examined whether HIIT using electrical stimulation (ES), which does not require whole-body exercise, improves muscle endurance in the skeletal muscle of 5/6 nephrectomized rats, a widely used animal model for CKD-related cachexia.Methods: Male Wistar rats (10 weeks old) were randomly assigned to a group of sham-operated (Sham) rats and a group of 5/6 nephrectomy (Nx) rats. HIIT was performed on plantar flexor muscles in vivo with supramaximal ES every other day for 4 weeks to assess muscle endurance, myosin heavy-chain isoforms, and mitochondrial respiratory function in Nx rats. A single session was also performed to identify upstream signaling pathways altered by HIIT using ES.
    Results: In the non-trained plantar flexor muscles from Nx rats, the muscle endurance was significantly lower than that in plantar flexor muscles from Sham rats. The proportion of myosin heavy chain IIa/x, mitochondrial content, mitochondrial respiratory capacity, and formation of mitochondrial respiratory supercomplexes in the plantaris muscle were also significantly decreased in the non-trained plantar flexor muscles from Nx rats than compared to those in plantar flexor muscles from Sham rats. Treatment with HIIT using ES for Nx rats significantly improved these molecular and functional changes to the same degrees as those in Sham rats. Furthermore, a single session of HIIT with ES significantly increased the phosphorylation levels of AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK), pathways that are essential for mitochondrial activation signaling by exercise, in the plantar muscles of both Nx and Sham rats.
    Conclusion: The findings suggest that HIIT using ES ameliorates muscle fatigue in Nx rats via restoration of mitochondrial respiratory dysfunction with activation of AMPK and p38 MAPK signaling. Our ES-based HIIT protocol can be performed without placing a burden on the whole body and be a promising intervention that is implemented even in conditions of reduced general performance status such as CKD-related cachexia.
    Keywords:  cachexia; chronic kidney disease; high-intensity interval training; mitochondria; muscle endurance
    DOI:  https://doi.org/10.3389/fphys.2024.1423504
  35. Am J Physiol Cell Physiol. 2024 Jul 09.
    Exercise as a tool to mitigate metabolic disease.
    Joao Victor Esteves, Kristin I Stanford.
      Metabolic diseases, notably obesity and type 2 diabetes, have reached alarming proportions and constitute a significant global health challenge, emphasizing the urgent need for effective preventive and therapeutic strategies. In contrast, exercise training emerges as a potent intervention, exerting numerous positive effects on metabolic health through adaptations to the metabolic tissues. Here, we reviewed the major features of our current understanding with respect to the intricate interplay between metabolic diseases and key metabolic tissues, including adipose tissue, skeletal muscle, and liver, describing some of the main underlying mechanisms driving pathogenesis, as well as the role of exercise to combat and treat obesity and metabolic disease.
    Keywords:  Exercise; adipose tissue; insulin resistance; metabolism; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpcell.00144.2024
  36. Int J Biol Sci. 2024 ;20(9): 3530-3543
    Epsti1 Regulates the Inflammatory Stage of Early Muscle Regeneration through STAT1-VCP Interaction.
    Jee Won Kim, Ju-Hyeon Bae, Ga-Yeon Go, Jae-Rin Lee, Yideul Jeong, Jun-Young Kim, Tae Hyun Kim, Yong Kee Kim, Jeung-Whan Han, Ji-Eun Oh, Myong-Joon Hahn, Jong-Sun Kang, Gyu-Un Bae.
      During muscle regeneration, interferon-gamma (IFN-γ) coordinates inflammatory responses critical for activation of quiescent muscle stem cells upon injury via the Janus kinase (JAK) - signal transducer and activator of transcription 1 (STAT1) pathway. Dysregulation of JAK-STAT1 signaling results in impaired muscle regeneration, leading to muscle dysfunction or muscle atrophy. Until now, the underlying molecular mechanism of how JAK-STAT1 signaling resolves during muscle regeneration remains largely elusive. Here, we demonstrate that epithelial-stromal interaction 1 (Epsti1), an interferon response gene, has a crucial role in regulating the IFN-γ-JAK-STAT1 signaling at early stage of muscle regeneration. Epsti1-deficient mice exhibit impaired muscle regeneration with elevated inflammation response. In addition, Epsti1-deficient myoblasts display aberrant interferon responses. Epsti1 interacts with valosin-containing protein (VCP) and mediates the proteasomal degradation of IFN-γ-activated STAT1, likely contributing to dampening STAT1-mediated inflammation. In line with the notion, mice lacking Epsti1 exhibit exacerbated muscle atrophy accompanied by increased inflammatory response in cancer cachexia model. Our study suggests a crucial function of Epsti1 in the resolution of IFN-γ-JAK-STAT1 signaling through interaction with VCP which provides insights into the unexplored mechanism of crosstalk between inflammatory response and muscle regeneration.
    Keywords:  Epsti1; IFN-γ-JAK-STAT1 pathway; Inflammatory response; Muscle regeneration; Ubiquitin-proteasomal degradation; VCP
    DOI:  https://doi.org/10.7150/ijbs.94675
  37. bioRxiv. 2024 Jun 25. pii: 2024.06.21.600113. [Epub ahead of print]
    Myo-optogenetics: optogenetic stimulation and electrical recording in skeletal muscles.
    Jeong Jun Kim, Isis S Wyche, William Olson, Jiaao Lu, Muhannad S Bakir, Samuel J Sober, Daniel H O'Connor.
      Complex movements involve highly coordinated control of local muscle elements. Highly controlled perturbations of motor outputs can reveal insights into the neural control of movements. Here we introduce an optogenetic method, compatible with electromyography (EMG) recordings, to perturb muscles in transgenic mice. By expressing channelrhodopsin in muscle fibers, we achieved noninvasive, focal activation of orofacial muscles, enabling detailed examination of the mechanical properties of optogenetically evoked jaw muscle contractions. We demonstrated simultaneous EMG recording and optical stimulation, revealing the electrophysiological characteristics of optogenetically triggered muscle activity. Additionally, we applied optogenetic activation of muscles in physiologically and behaviorally relevant settings, mapping precise muscle actions and perturbing active behaviors. Our findings highlight the potential of muscle optogenetics to precisely manipulate muscle activity, offering a powerful tool for probing neuromuscular control systems and advancing our understanding of motor control.
    DOI:  https://doi.org/10.1101/2024.06.21.600113
  38. Int J Mol Sci. 2024 Jun 21. pii: 6819. [Epub ahead of print]25(13):
    Effect of mTORC Agonism via MHY1485 with and without Rapamycin on C2C12 Myotube Metabolism.
    Norah E Cook, Macey R McGovern, Toheed Zaman, Pamela M Lundin, Roger A Vaughan.
      The mechanistic target of rapamycin complex (mTORC) regulates protein synthesis and can be activated by branched-chain amino acids (BCAAs). mTORC has also been implicated in the regulation of mitochondrial metabolism and BCAA catabolism. Some speculate that mTORC overactivation by BCAAs may contribute to insulin resistance. The present experiments assessed the effect of mTORC activation on myotube metabolism and insulin sensitivity using the mTORC agonist MHY1485, which does not share structural similarities with BCAAs.METHODS: C2C12 myotubes were treated with MHY1485 or DMSO control both with and without rapamycin. Gene expression was assessed using qRT-PCR and insulin sensitivity and protein expression by western blot. Glycolytic and mitochondrial metabolism were measured by extracellular acidification rate and oxygen consumption. Mitochondrial and lipid content were analyzed by fluorescent staining. Liquid chromatography-mass spectrometry was used to assess extracellular BCAAs.
    RESULTS: Rapamycin reduced p-mTORC expression, mitochondrial content, and mitochondrial function. Surprisingly, MHY1485 did not alter p-mTORC expression or cell metabolism. Neither treatment altered indicators of BCAA metabolism or extracellular BCAA content.
    CONCLUSION: Collectively, inhibition of mTORC via rapamycin reduces myotube metabolism and mitochondrial content but not BCAA metabolism. The lack of p-mTORC activation by MHY1485 is a limitation of these experiments and warrants additional investigation.
    Keywords:  branched-chain amino acids; isoleucine; leucine; mitochondrial function; skeletal muscle; valine
    DOI:  https://doi.org/10.3390/ijms25136819
  39. Cancer Metastasis Rev. 2024 Jul 12.
    Striated muscle: an inadequate soil for cancers.
    Alastair A E Saunders, Rachel E Thomson, Craig A Goodman, Robin L Anderson, Paul Gregorevic.
      Many organs of the body are susceptible to cancer development. However, striated muscles-which include skeletal and cardiac muscles-are rarely the sites of primary cancers. Most deaths from cancer arise due to complications associated with the development of secondary metastatic tumours, for which there are few effective therapies. However, as with primary cancers, the establishment of metastatic tumours in striated muscle accounts for a disproportionately small fraction of secondary tumours, relative to the proportion of body composition. Examining why primary and metastatic cancers are comparatively rare in striated muscle presents an opportunity to better understand mechanisms that can influence cancer cell biology. To gain insights into the incidence and distribution of muscle metastases, this review presents a definitive summary of the 210 case studies of metastasis in muscle published since 2010. To examine why metastases rarely form in muscles, this review considers the mechanisms currently proposed to render muscle an inhospitable environment for cancers. The "seed and soil" hypothesis proposes that tissues' differences in susceptibility to metastatic colonization are due to differing host microenvironments that promote or suppress metastatic growth to varying degrees. As such, the "soil" within muscle may not be conducive to cancer growth. Gaining a greater understanding of the mechanisms that underpin the resistance of muscles to cancer may provide new insights into mechanisms of tumour growth and progression, and offer opportunities to leverage insights into the development of interventions with the potential to inhibit metastasis in susceptible tissues.
    Keywords:  Cancer; Cardiac muscle; Metastasis; Skeletal muscle; Striated muscle
    DOI:  https://doi.org/10.1007/s10555-024-10199-2
  40. FASEB J. 2024 Jul 31. 38(14): e23808
    Unveiling the role of circRBBP7 in myoblast proliferation and differentiation: A novel regulator of muscle development.
    Yufeng Yang, Kongwei Huang, Hancai Jiang, Shuwan Wang, Xiaoxian Xu, Yang Liu, Qingyou Liu, Mingsong Wei, Zhipeng Li.
      Muscle development is a multistep process regulated by diverse gene networks, and circRNAs are considered novel regulators mediating myogenesis. Here, we systematically analyzed the role and underlying regulatory mechanisms of circRBBP7 in myoblast proliferation and differentiation. Results showed that circRBBP7 has a typical circular structure and encodes a 13 -kDa protein. By performing circRBBP7 overexpression and RNA interference, we found that the function of circRBBP7 was positively correlated with the proliferation and differentiation of myoblasts. Using RNA sequencing, we identified 1633 and 532 differentially expressed genes (DEGs) during myoblast proliferation or differentiation, respectively. The DEGs were found mainly enriched in cell cycle- and skeletal muscle development-related pathways, such as the MDM2/p53 and PI3K-Akt signaling pathways. Further co-IP and IF co-localization analysis revealed that VEGFR-1 is a target of circRBBP7 in myoblasts. qRT-PCR and WB analysis further confirmed the positive correlation between VEGFR-1 and circRBBP7. Moreover, we found that in vivo transfection of circRBBP7 into injured muscle tissues significantly promoted the regeneration and repair of myofibers in mice. Therefore, we speculate that circRBBP7 may affect the activity of MDM2 by targeting VEGFR-1, altering the expression of muscle development-related genes by mediating p53 degradation, and ultimately promoting myoblast development and muscle regeneration. This study provides essential evidence that circRBBP7 can serve as a potential target for myogenesis regulation and a reference for the application of circRBBP7 in cattle genetic breeding and muscle injury treatment.
    Keywords:   VEGFR‐1 ; circRBBP7; muscle repair; myogenesis; proliferation and differentiation
    DOI:  https://doi.org/10.1096/fj.202302599RR
  41. J Physiol. 2024 Jul 06.
    Marcinek and Ferrucci response to Lanza et al.
    David J Marcinek, Luigi Ferrucci.
      
    Keywords:  ageing; mitochondria; mobility; muscle energetics
    DOI:  https://doi.org/10.1113/JP286696
  42. JCI Insight. 2024 May 30. pii: e176383. [Epub ahead of print]9(13):
    Protein biomarker signature in patients with spinal and bulbar muscular atrophy.
    Andrew Tn Tebbenkamp, Spencer B Huggett, Vittoria Lombardi, Luca Zampedri, Abdullah AlQahtani, Angela Kokkinis, Andrea Malaspina, Carlo Rinaldi, Christopher Grunseich, Pietro Fratta, Vissia Viglietta.
      Spinal and bulbar muscular atrophy (SBMA) is a slowly progressing disease with limited sensitive biomarkers that support clinical research. We analyzed plasma and serum samples from patients with SBMA and matched healthy controls in multiple cohorts, identifying 40 highly reproducible SBMA-associated proteins out of nearly 3,000 measured. These proteins were robustly enriched in gene sets of skeletal muscle expression and processes related to mitochondria and calcium signaling. Many proteins outperformed currently used clinical laboratory tests (e.g., creatine kinase [CK]) in distinguishing patients from controls and in their correlations with clinical and functional traits in patients. Two of the 40 proteins, Ectodysplasin A2 receptor (EDA2R) and Repulsive guidance molecule A (RGMA), were found to be associated with decreased survival and body weight in a mouse model of SBMA. In summary, we identified what we believe to be a robust and novel set of fluid protein biomarkers in SBMA that are linked with relevant disease features in patients and in a mouse model of disease. Changes in these SBMA-associated proteins could be used as an early predictor of treatment effects in clinical trials.
    Keywords:  Genetic diseases; Muscle biology; Neuromuscular disease; Neuroscience; Proteomics
    DOI:  https://doi.org/10.1172/jci.insight.176383
  43. Sci Immunol. 2024 Jul 12. 9(97): eadm7908
    Infection and chronic disease activate a systemic brain-muscle signaling axis.
    Shuo Yang, Meijie Tian, Yulong Dai, Rong Wang, Shigehiro Yamada, Shengyong Feng, Yunyun Wang, Deepak Chhangani, Tiffany Ou, Wenle Li, Xuan Guo, Jennifer McAdow, Diego E Rincon-Limas, Xin Yin, Wanbo Tai, Gong Cheng, Aaron Johnson.
      Infections and neurodegenerative diseases induce neuroinflammation, but affected individuals often show nonneural symptoms including muscle pain and muscle fatigue. The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood. We developed multiple models to investigate the impact of CNS stressors on motor function and found that Escherichia coli infections and SARS-CoV-2 protein expression caused reactive oxygen species (ROS) to accumulate in the brain. ROS induced expression of the cytokine Unpaired 3 (Upd3) in Drosophila and its ortholog, IL-6, in mice. CNS-derived Upd3/IL-6 activated the JAK-STAT pathway in skeletal muscle, which caused muscle mitochondrial dysfunction and impaired motor function. We observed similar phenotypes after expressing toxic amyloid-β (Aβ42) in the CNS. Infection and chronic disease therefore activate a systemic brain-muscle signaling axis in which CNS-derived cytokines bypass the connectome and directly regulate muscle physiology, highlighting IL-6 as a therapeutic target to treat disease-associated muscle dysfunction.
    DOI:  https://doi.org/10.1126/sciimmunol.adm7908
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