bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2025–02–23
34 papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Mitophagy is required to protect against excessive skeletal muscle atrophy following hindlimb immobilization.
  2. Altered relaxation and Mitochondria-Endoplasmic Reticulum Contacts Precede Major (Mal)adaptations in Aging Skeletal Muscle and are Prevented by Exercise.
  3. Increased Matrix Stiffness Promotes Slow Muscle Fibre Regeneration After Skeletal Muscle Injury.
  4. A primer on global molecular responses to exercise in skeletal muscle: Omics in focus.
  5. CRISPR/Cas9-Targeted Myostatin Deletion Improves the Myogenic Differentiation Parameters for Muscle-Derived Stem Cells in Mice.
  6. Keratocan Improves Muscle Wasting in Sarcopenia by Promoting Skeletal Muscle Development and Fast-Twitch Fibre Synthesis.
  7. Conditional Dystrophin ablation in the skeletal muscle and brain causes profound effects on muscle function, neurobehavior, and extracellular matrix pathways.
  8. ArfGAP3 Protects Mitochondrial Function and Promotes Autophagy Through Rab5a-Mediated Signals in Ageing Skeletal Muscle.
  9. Delivery of A Chemically Modified Noncoding RNA Domain Improves Dystrophic Myotube Function.
  10. Microgravity Accelerates Skeletal Muscle Degeneration: Functional and Transcriptomic Insights from a Muscle Lab-on-Chip Model Onboard the ISS.
  11. Exploring the therapeutic potential of fibroadipogenic progenitors in muscle disease.
  12. Endoplasmic reticulum stress and unfolded protein response: Roles in skeletal muscle atrophy.
  13. Human skeletal muscle fiber heterogeneity beyond myosin heavy chains.
  14. GDF15 Neutralization Ameliorates Muscle Atrophy and Exercise Intolerance in a Mouse Model of Mitochondrial Myopathy.
  15. Muscle-specific ERRγ activation mitigates muscle atrophy after ACL injury.
  16. Human iPSC-Derived Motor Neuron Innervation Enhances the Differentiation of Muscle Bundles Engineered with Benchtop Fabrication Techniques.
  17. Decoding CKD-induced muscle atrophy through the critical role of lncRNA GAS5 and pyroptosis.
  18. Creatine transporter (SLC6A8) knockout mice exhibit reduced muscle performance, disrupted mitochondrial Ca2+ homeostasis, and severe muscle atrophy.
  19. Protein-energy wasting in chronic kidney disease: mechanisms responsible for loss of muscle mass and function.
  20. Healthy Aging Metabolomic and Proteomic Signatures Across Multiple Physiological Compartments.
  21. The link between Mitochondria and Sarcopenia.
  22. Piezo1 channels enhance anabolic signaling activation induced by electrical stimulation of cultured myotubes.
  23. Low-Magnitude High-Frequency Vibration Attenuates Sarcopenia by Modulating Mitochondrial Quality Control via Inhibiting miR-378.
  24. PDZRN3 regulates adipogenesis of mesenchymal progenitors in muscle.
  25. Using physiologically-based models to predict in vivo skeletal muscle energetics.
  26. FOXO regulation of TXNIP induces ferroptosis in satellite cells by inhibiting glutathione metabolism, promoting Sarcopenia.
  27. Irisin: muscle's novel player in endoplasmic reticulum stress and disease.
  28. HMGB1 in Septic Muscle Atrophy: Roles and Therapeutic Potential for Muscle Atrophy and Regeneration.
  29. Epigenetic small molecule screening identifies a new HDACi compound for ameliorating Duchenne muscular dystrophy.
  30. PI3KC2β depletion rescues endosomal trafficking defects in Mtm1 knockout skeletal muscle cells.
  31. Deuterium-reinforced polyunsaturated fatty acids protect against muscle atrophy by STZ-induced diabetic mice.
  32. Exercise intensity matters: A review on evaluating the effects of aerobic exercise intensity on muscle-derived neuroprotective myokines.
  33. Muscle-specific gene editing improves molecular and phenotypic defects in a mouse model of myotonic dystrophy type 1.
  34. Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST.
  1. J Biomed Sci. 2025 Feb 18. 32(1): 29
    Mitophagy is required to protect against excessive skeletal muscle atrophy following hindlimb immobilization.
    Fasih A Rahman, Mackenzie Q Graham, Amanda M Adam, Emma S Juracic, A Russell Tupling, Joe Quadrilatero.
       BACKGROUND: Skeletal muscle atrophy involves significant remodeling of fibers and is characterized by deficits in mitochondrial content and function. These changes are intimately connected to shifts in mitochondrial turnover, encompassing processes such as mitophagy and mitochondrial biogenesis. However, the role of these mitochondrial turnover processes in muscle atrophy remains poorly understood.
    METHODS: We used a novel mitophagy reporter model, mt-Keima mice, to perform hindlimb immobilization and accurately measure mitophagy. A comprehensive set of analyses were conducted to investigate biochemical and molecular changes at the muscle and mitochondrial levels. We also performed image analyses to determine mitophagic flux. To further explore the role of mitophagy in immobilization-induced atrophy, we treated animals with N-acetylcysteine (NAC; 150 mg/kg/day) to modify reactive oxygen species (ROS) signaling and colchicine (0.4 mg/kg/day) to inhibit autophagy.
    RESULTS: Our study revealed that hindlimb immobilization leads to muscle weakness and atrophy of fast-twitch muscle fibers (types IIA, IIX, and IIB), with recovery observed in IIA fibers following remobilization. This atrophy was accompanied by a significant increase in mitophagic flux. Additionally, immobilization induced notable mitochondrial dysfunction, as shown by diminished respiration, increased mitochondrial ROS, and greater whole muscle lipid peroxidation. Treatment of immobilized mice with NAC enhanced mitochondrial respiration and reduced ROS generation but suppressed mitophagic flux and intensified atrophy of type IIX and IIB fibers. Additionally, administration of colchicine to immobilized mice suppressed mitophagic flux, which also exacerbated atrophy of IIX and IIB fibers. Colchicine treatment led to significant reductions in mitochondrial function, accompanied by CASP9 and CASP3 activation.
    CONCLUSION: These findings emphasize the role of mitophagy in limiting excessive muscle atrophy during immobilization. Targeting mitophagy may offer new strategies to preserve muscle function during prolonged periods of immobilization.
    Keywords:  Apoptosis; BNIP3; Disuse atrophy; Mitochondria; Mitophagy; Skeletal muscle
    DOI:  https://doi.org/10.1186/s12929-025-01118-w
  2. bioRxiv. 2025 Feb 05. pii: 2025.01.14.633043. [Epub ahead of print]
    Altered relaxation and Mitochondria-Endoplasmic Reticulum Contacts Precede Major (Mal)adaptations in Aging Skeletal Muscle and are Prevented by Exercise.
    Ryan J Allen, Ana Kronemberger, Qian Shi, Marshall Pope, Elizabeth Cuadra-Muñoz, Wangkuk Son, Long-Sheng Song, Ethan J Anderson, Renata O Pereira, Vitor A Lira.
      Sarcopenia, or age-related muscle dysfunction, contributes to morbidity and mortality. Besides decreases in muscle force, sarcopenia is associated with atrophy and fast-to-slow fiber type switching, which is typically secondary to denervation in humans and rodents. However, very little is known about cellular changes preceding these important (mal)adaptations. To this matter, mitochondria and the sarcoplasmic reticulum are critical for tension generation in myofibers. They physically interact at the boundaries of sarcomeres forming subcellular hubs called mitochondria-endo/sarcoplasmic reticulum contacts (MERCs). Yet, whether changes at MERCs ultrastructure and proteome occur early in aging is unknown. Here, studying young adult and older mice we reveal that aging slows muscle relaxation leading to longer excitation-contraction-relaxation (ECR) cycles before maximal force decreases and fast-to-slow fiber switching takes place. We reveal that muscle MERC ultrastructure and mitochondria-associated ER membrane (MAM) protein composition are also affected early in aging and are closely associated with rate of muscle relaxation. Additionally, we demonstrate that regular exercise preserves muscle relaxation rate and MERC ultrastructure in early aging. Finally, we profile a set of muscle MAM proteins involved in energy metabolism, protein quality control, Ca 2+ homeostasis, cytoskeleton integrity and redox balance that are inversely regulated early in aging and by exercise. These may represent new targets to preserve muscle function in aging individuals.
    DOI:  https://doi.org/10.1101/2025.01.14.633043
  3. J Cell Mol Med. 2025 Feb;29(4): e70423
    Increased Matrix Stiffness Promotes Slow Muscle Fibre Regeneration After Skeletal Muscle Injury.
    Dongmei Wang, Jiahong Wu, Zeyu Xu, Jinning Jia, Yimei Lai, Zhihua He.
      The global prevalence of skeletal muscle diseases has progressively escalated in recent years. This study aimed to explore the potential role of matrix stiffness in the repair mechanisms following skeletal muscle injury. We observed an increase in muscle stiffness, a significant rise in the number of type I muscle fibres and a notable elevation in mRNA expression levels of Myh7/2 alongside a decrease in Myh1/4 on day 3 post tibialis anterior muscle injury. To replicate these in vivo changes, C2C12 cells were cultured under high matrix stiffness conditions, and compared to those on low matrix stiffness, the C2C12 cells cultured on high matrix stiffness showed increased expression levels of Myh7/2 mRNA and production levels of MYH7/2, indicating differentiation into slow-twitch muscle fibre types. Furthermore, up-regulation of DRP1 phosphorylation along with elevated F-actin fluorescence intensity and RHOA and ROCK1 production indicates that high matrix stiffness induces cytoskeletal remodelling to regulate mitochondrial fission processes. Our data also revealed up-regulation in mRNA expression level for Actb, phosphorylation level for DRP1, mitochondrial quantity and MYH7/2 production level. Importantly, these effects were effectively reversed by the application of ROCK inhibitor Y-27632, highlighting that targeting cytoskeletal dynamics can modulate myogenic differentiation pathways within C2C12 cells. These findings provide valuable insights into how matrix stiffness influences fibre type transformation during skeletal muscle injury repair while suggesting potential therapeutic targets for intervention.
    Keywords:  RHO/ROCK pathway; cytoskeleton; extracellular matrix; mitochondrial fission; muscle fibre type; stiffness
    DOI:  https://doi.org/10.1111/jcmm.70423
  4. J Sport Health Sci. 2025 Feb 15. pii: S2095-2546(25)00007-9. [Epub ahead of print] 101029
    A primer on global molecular responses to exercise in skeletal muscle: Omics in focus.
    Kevin A Murach, James R Bagley.
      Advances in skeletal muscle omics has expanded our understanding of exercise-induced adaptations at the molecular level. Over the past 2 decades, transcriptome studies in muscle have detailed acute and chronic responses to resistance, endurance, and concurrent exercise, focusing on variables such as training status, nutrition, age, sex, and metabolic health profile. Multi-omics approaches, such as the integration of transcriptomic and epigenetic data, along with emerging ribosomal RNA sequencing advancements, have further provided insights into how skeletal muscle adapts to exercise across the lifespan. Downstream of the transcriptome, proteomic and phosphoproteomic studies have identified novel regulators of exercise adaptations, while single-cell/nucleus and spatial sequencing technologies promise to evolve our understanding of cellular specialization and communication in and around skeletal muscle cells. This narrative review highlights (a) the historical foundations of exercise omics in skeletal muscle, (b) current research at 3 layers of the omics cascade (DNA, RNA, and protein), and (c) applications of single-cell omics and spatial sequencing technologies to study skeletal muscle adaptation to exercise. Further elaboration of muscle's global molecular footprint using multi-omics methods will help researchers and practitioners develop more effective and targeted approaches to improve skeletal muscle health as well as athletic performance.
    Keywords:  Epigenomics; Phosphoproteomics; Proteomics; Single cell; Transcriptomics
    DOI:  https://doi.org/10.1016/j.jshs.2025.101029
  5. J Dev Biol. 2025 Feb 11. pii: 5. [Epub ahead of print]13(1):
    CRISPR/Cas9-Targeted Myostatin Deletion Improves the Myogenic Differentiation Parameters for Muscle-Derived Stem Cells in Mice.
    Mohamed I Elashry, Victoria C Schneider, Manuela Heimann, Sabine Wenisch, Stefan Arnhold.
      Skeletal muscle plays a pivotal role in physical activity, protein storage and energy utilization. Skeletal muscle wasting due to immobilization, aging, muscular dystrophy and cancer cachexia has negative impacts on the quality of life. The deletion of myostatin, a growth and differentiation factor-8 (GDF-8) augments muscle mass through hyperplasia and hypertrophy of muscle fibers. The present study examines the impact of myostatin deletion using CRISPR/Cas9 editing on the myogenic differentiation (MD) of C2C12 muscle stem cells. A total of five myostatin loci were targeted using guided RNAs that had been previously cloned into a vector. The clones were transfected in C2C12 cells via electroporation. The cell viability and MD of myostatin-edited clones (Mstn-/-) were compared with C2C12 (Mstn+/+) using a series of assays, including MTT, sulforhodamine B, immunocytochemistry, morphometric analysis and RT-qPCR. The clones sequenced showed evidence of nucleotides deletion in Mstn-/- cells. Mstn-/- cells demonstrated a normal physiological performance and lack of cytotoxicity. Myostatin depletion promoted the myogenic commitment as evidenced by upregulated MyoD and myogenin expression. The number of MyoD-positive cells was increased in the differentiated Mstn-/- clones. The Mstn-/- editing upregulates both mTOR and MyH expression, as well as increasing the size of myotubes. The differentiation of Mstn-/- cells upregulates ActRIIb; in contrast, it downregulates decorin expression. The data provide evidence of successful CRISPR/Cas9-mediated myostatin deletion. In addition, targeting myostatin could be a beneficial therapeutic strategy to promote MD and to restore muscle loss. In conclusion, the data suggest that myostatin editing using CRISPR/Cas9 could be a potential therapeutic manipulation to improve the regenerative capacity of muscle stem cells before in vivo application.
    Keywords:  CRISPR/Cas9; muscle stem cells; myogenic differentiation; myostatin
    DOI:  https://doi.org/10.3390/jdb13010005
  6. J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13724
    Keratocan Improves Muscle Wasting in Sarcopenia by Promoting Skeletal Muscle Development and Fast-Twitch Fibre Synthesis.
    Xu Chen, Yanyan Zhang, Zhibo Deng, Chao Song, Linhai Yang, Rongsheng Zhang, Peng Zhang, Yu Xiu, Yibin Su, Jun Luo, Jie Xu, Hanhao Dai.
       BACKGROUND: Osteosarcopenia refers to the co-occurrence of osteoporosis and sarcopenia, which are characterized by progressive bone density and muscle mass loss, respectively. Muscle and bone are regulated by many common genes and pathways, enabling potential co-treatment. Because keratocan protects against osteoporosis, we hypothesized it may also protect against sarcopenia, implying a new co-intervention target. This study aimed to elucidate the role and molecular mechanisms of keratocan in skeletal muscle.
    METHODS: We analysed keratocan expression in the muscles of aged mice and patients with osteosarcopenia and during the differentiation of C2C12 myoblasts. The regulatory role of keratocan was assessed by knocking down or overexpressing keratocan in C2C12 cells and examining any effects on myogenic proliferation and differentiation. RNA sequencing analysis was also performed on these cells. The relationship between keratocan and enriched signalling pathways was verified using pathway inhibitors or agonists. Finally, adeno-associated virus-9 containing a muscle-specific promoter was injected into SAMP8 senile mice to observe the effects of keratocan overexpression.
    RESULTS: Keratocan expression was significantly lower in the skeletal muscles of aging mice (-2.02-fold, p < 0.01) and patients with osteosarcopenia (-1.78-fold, p < 0.001) compared with that in controls. Keratocan overexpression resulted in a significant increase in the proliferation indices CCND1 (+1.43-fold, p < 0.001), Ki67 (+2.30-fold, p < 0.001) and PCNA (+1.975-fold, p < 0.01) and the differentiation indices MyoD1 (+2.156-fold, p < 0.001), MyoG (+1.52-fold, p < 0.05) and myosin heavy chain (MyHC; +2.849-fold, p < 0.01); conversely, the muscle atrophy indices MuRF-1 (-30%, p < 0.01), atrogin-1 (-87%, p < 0.01) and myostatin (-24%, p < 0.01) were significantly decreased. PI3K/AKT/mTOR was identified as a potential pathway for keratocan regulation in C2C12 cells. PI3K inhibitor LY294002 reversed the promotion of myogenesis by keratocan overexpression, while PI3K activator 740Y-P reversed the inhibitory effect of keratocan knockdown on myogenesis, promoting myofibre development and ameliorating muscle atrophy in SAMP8 aging mice. This was evidenced by increased mean muscle cross-sectional area (+38%, p < 0.0001) and muscle mass (+7%, p < 0.01) and decreased fibrosis (-40%, p < 0.01). Furthermore, keratocan facilitated the conversion of slow-to-fast muscle fibres through the PI3K/AKT/mTOR pathway, characterized by significantly increased grip strength (+42%, p < 0.01) and maximum running speed (+19%, p < 0.001), and decreased fatigue time (+13%, p < 0.05).
    CONCLUSIONS: Keratocan ameliorates muscle atrophy by activating the PI3K/AKT/mTOR pathway, promoting muscle satellite cell proliferation and myogenic differentiation, and facilitating the conversion of slow-to-fast muscle fibres. Our findings demonstrate the potential of keratocan as a novel therapeutic target for osteosarcopenia.
    Keywords:  PI3K/AKT/mTOR pathway; keratocan; osteoporosis; osteosarcopenia; sarcopenia
    DOI:  https://doi.org/10.1002/jcsm.13724
  7. bioRxiv. 2025 Feb 09. pii: 2025.01.30.635777. [Epub ahead of print]
    Conditional Dystrophin ablation in the skeletal muscle and brain causes profound effects on muscle function, neurobehavior, and extracellular matrix pathways.
    Muthukumar Karuppasamy, Katherine G English, James R Conner, Shelby N Rorrer, Michael A Lopez, David K Crossman, Jodi R Paul, Miguel A Monreal-Gutierrez, Karen L Gamble, Karyn A Esser, Jeffrey J Widrick, Louis M Kunkel, Matthew S Alexander.
      Duchenne muscular dystrophy (DMD) patients suffer from skeletal and cardiopulmonary weakness, and interestingly up to one third are diagnosed on the autism spectrum. Dystrophin is an essential protein for regulating the transmission of intracellular force to the extracellular matrix within the skeletal muscle, but also plays key roles in neurobehavior and cognitive function. The mouse dystrophin gene (also abbreviated Dmd ) is X-linked and has several isoforms with tissue-specific expression, including the large Dp427m muscle transcript found in heart and skeletal muscle, and the Dp427c transcript that encodes the brain-specific dystrophin cerebellar protein. Understanding the functional requirements and pathways that are affected by dystrophin loss will impact dystrophin replacement gene therapy and exon-skipping correction strategies. We generated conditional Dystrophin knockout mice by targeting exon 52 of the mouse Dystrophin ( Dmd flox52 ) locus. We generated dystrophin constitutive and inducible myofiber knockout ( Dmd mKO) mice to evaluate the tissue-specific function of the large skeletal muscle dystrophin isoform. Constitutive embryonic deletion of the Dystrophin gene exclusively in skeletal myofibers resulted in a severe skeletal muscle myopathy, dystrophic histopathology, and functional deficits compared to the mdx mouse. Transcriptomic analysis of skeletal myofibers of the Dmd mKO mice revealed the dysregulation of key extracellular matrix and cytokine signaling pathways. Separately, we generated Purkinje neuron cerebellar dystrophin knockout ( Dmd :Pcp2 KO) mice that displayed neurobehavioral deficits in social approach, social memory, and spatial navigation and working memory. These studies reveal the essential requirement for dystrophin expression in both the skeletal muscle and brain for normal physiological and neurobehavioral function.
    Significance Statement: Duchenne muscular dystrophy is caused by the lack of a functional dystrophin protein in muscle. The large dystrophin (Dp427m) isoform is expressed in skeletal, cardiac, and smooth muscle, but its tissue-specific requirements remain unknown. We generated and characterized a conditional skeletal muscle knockout mouse ( Dmd mKO). Constitutive embryonic genetic ablation of skeletal muscle Dystrophin resulted in muscle histopathologies similar to the mdx mouse, while postnatal muscle Dystrophin ablation resulted in milder pathologies. Ablating cerebellar Dystrophin Dp427c using a Pcp2/L7 -Cre driver resulted in sociobehavioral defects. Transcriptomic analysis of the Dmd mKO mice showed a severe reduction of extracellular matrix and cytokine signaling pathways. Our study reveals an essential role for skeletal muscle dystrophin and identifies essential pathways for modulation using dystrophin-replacement therapies.
    DOI:  https://doi.org/10.1101/2025.01.30.635777
  8. J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13725
    ArfGAP3 Protects Mitochondrial Function and Promotes Autophagy Through Rab5a-Mediated Signals in Ageing Skeletal Muscle.
    Mao Chen, Xiaoyu Huang, Bingshu Li, Ya Xiao, Liying Chen, Fangyi Zhu, Shasha Hong, Jianming Tang, Suting Li, Jie Min, Wenyi Jin, Yubiao Zhang, Lian Yang, Yang Li, Shufei Zhang, Li Hong.
       BACKGROUND: Few researches have investigated the molecular mechanism responsible for the age-related loss of the pelvic floor muscle (PFM) mass and functionality-a pivotal contributor to pelvic organ prolapse and diminished physical well-being. ADP ribosylation factor GTPase activating protein 3 (ArfGAP3) is a member of ArfGAPs, which regulates the vesicular trafficking pathway and intracellular proteins transporting. However, its effects on skeletal muscle ageing remain largely unknown.
    METHODS: Mouse models of natural ageing and D-gal (D-galactose)-induced ageing were subject to analyse the structure, function and pathological alterations of the PFM and the expression of ArfGAP3. Stable ArfGAP3 knockdown and overexpression C2C12 cell lines were established to investigate the anti-senescence effects of ArfGAP3 and the underlying mechanisms in ageing process, complemented by Rab5a genetic intervention and mRFP-GFP-LC3 adenoviral particles transfection. In vivo experiments entailed ArfGAP3 overexpression in mice alongside autophagy inhibitor treatment, with assessments encompassing tissue mass, bladder leak point pressure (BLPP), submicroscopic structure, antioxidative stress system and muscle regeneration.
    RESULTS: Aged (24-month-old) mice exhibited significant physiological alterations in PFMs, including decreased muscle mass, diminished cross-sectional area (CSA), deteriorated supporting function (as evidenced by reduced BLPP), impaired autophagy and increased levels of oxidative stress (p < 0.001). Utilizing ageing C2C12 model, we observed a dose-dependent relationship between D-gal induction and cellular senescence, impaired differentiation and mitochondrial damage. Remarkably, the expression levels of ArfGAP3 were markedly downregulated in both in vitro and in vivo ageing models. Knockdown of ArfGAP3 exacerbated impaired differentiation potential and induced aberrant mitochondrial morphology and functional dysfunction in ageing C2C12 myoblasts, whereas ArfGAP3 overexpression largely mitigated these effects. Mechanistically, our findings revealed an interplay between ArfGAP3 and Rab5a, indicating their coordinated regulation. ArfGAP3-mediated activation of Rab5a-associated autophagy and IRS1-AKT-mTOR signalling pathways during cellular senescence and myogenesis was identified, leading to enhanced autophagic flux and improved resistance to oxidative stress. In vivo, ArfGAP3 overexpression ameliorated D-gal-induced loss of muscle mass and function, while promoting antioxidant responses and muscle regeneration in mice. However, these protective effects of ArfGAP3 overexpression were extinguished by autophagy inhibition.
    CONCLUSIONS: Our study uncovers the significant role of ArfGAP3 in enhancing differentiation capacity and mitochondrial function through mediating Rab5a expression to activate IRS1-AKT-mTOR signalling pathways and promote autophagy during the ageing process. These findings underscore the potential of ArfGAP3 as a promising therapeutic target for ameliorating the decline in skeletal muscle function associated with ageing.
    Keywords:  ArfGAP3; Rab5a; ageing; autophagy; pelvic floor muscle
    DOI:  https://doi.org/10.1002/jcsm.13725
  9. Adv Sci (Weinh). 2025 Feb 17. e2410908
    Delivery of A Chemically Modified Noncoding RNA Domain Improves Dystrophic Myotube Function.
    Zeinabou Niasse-Sy, Bo Zhao, Ajda Lenardič, Huyen Thuc Tran Luong, Ori Bar-Nur, Johan Auwerx, Martin Wohlwend.
      Fast twitch muscle fibers are prone to degradation in skeletal muscle pathologies, such as sarcopenia and muscular dystrophies. We previously showed that the exercise-induced long noncoding RNA CYTOR promotes fast-twitch myogenesis. Here, we identify an independent functional element within human CYTOR, and optimize its RNA delivery. In human primary myoblasts exogenous CYTOR exon 2 recapitulates the effect of full-length CYTOR by boosting fast-twitch myogenic differentiation. Furthermore, chemically modified CYTORexon2 RNAΨU (N1-me-PseudoU, 7-methyl guanosine 5'Cap, polyA) enhances RNA stability and reduces immunogenicity to CYTORexon2 RNA. Viral- or chemically optimized RNA-mediated CYTORexon2 administration drives commitment toward myogenic maturation in Duchenne muscular dystrophy-derived primary myoblasts, myogenic progenitor cells, and mouse embryonic stem cells. Furthermore, CYTORexon2,ΨU improves key disease characteristics in dystrophic myotubes, including calcium handling and mitochondrial bioenergetics. In summary, we identify CYTOR exon 2 as the functional domain of CYTOR that can be delivered in a disease context using chemical modifications. This is of particular importance given the susceptibility of fast muscle fibers in different muscle pathologies such as aging and dystrophies, and the oncogenic effect of CYTOR exon 1. This study, therefore, highlights the potential of identifying functional domains in noncoding RNAs. Delivery, or targeting of RNA domains might constitute next-generation RNA therapeutics.
    Keywords:  CYTOR; RNA structure; aging; differentiation; dystrophy; functional domain; long noncoding RNA; myoblast; myogenesis; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1002/advs.202410908
  10. bioRxiv. 2025 Jan 27. pii: 2025.01.26.634580. [Epub ahead of print]
    Microgravity Accelerates Skeletal Muscle Degeneration: Functional and Transcriptomic Insights from a Muscle Lab-on-Chip Model Onboard the ISS.
    Maddalena Parafati, Zon Thwin, Legrand K Malany, Paul M Coen, Siobhan Malany.
      Microgravity accelerates skeletal muscle degeneration, mimicking aging, yet its effects on human muscle cell function and signaling remain underexplored. Using a muscle lab-on-chip model onboard the International Space Station, we examined how microgravity and electrically stimulated contractions influence muscle biology and age-related muscle changes. Our 3D bioengineered muscle model, cultured for 21 days (12 days in microgravity), included myobundles from young, active and older, sedentary individuals, with and without electrically stimulated contraction. Real-time data collected within an autonomous Space Tango CubeLab TM showed reduced contraction magnitude in microgravity. Global transcriptomic analysis revealed increased gene expression and particularly mitochondrial-related gene expression in microgravity for the electrically stimulated younger myobundles, while the older myobundles were less responsive. Moreover, a comparative analysis using a skeletal muscle aging gene expression database revealed that certain age-induced genes showed changes in expression in myobundles from the younger cohort when exposed to microgravity, whereas these genes remained unchanged in myobundles from the older cohort. Younger, electrically stimulated myobundles in microgravity exhibited higher expression of 45 aging genes involved in key aging pathways related to inflammation and immune function, mitochondrial dysfunction, and cellular stress; and decreased expression of 41 aging genes associated with inflammation, and cell growth. This study highlights a unique age-related molecular signature in muscle cells exposed to microgravity and underscores electrical stimulation as a potential countermeasure. These insights advance understanding of skeletal muscle aging and microgravity-induced degeneration, informing strategies for mitigating age-related muscle atrophy in space and on Earth.
    DOI:  https://doi.org/10.1101/2025.01.26.634580
  11. J Neuromuscul Dis. 2025 Jan-Feb;12(1):12(1): 22143602241298545
    Exploring the therapeutic potential of fibroadipogenic progenitors in muscle disease.
    Marshall W Hogarth, Medha P Kurukunda, Karim Ismat, Prech Uapinyoying, Jyoti K Jaiswal.
      Skeletal muscle relies on its inherent self-repair ability to withstand continuous mechanical damage. Myofiber-intrinsic processes facilitate the repair of damage to sarcolemma and sarcomeres, but it is the coordinated interaction between muscle-resident satellite and stromal cells that are crucial in the regeneration of muscles to replace the lost muscle fibers. Fibroadipogenic progenitors (FAPs), are muscle-resident mesenchymal cells that are notable for their role in creating the dynamic stromal niche required to support long-term muscle homeostasis and regeneration. While FAP-mediated extracellular matrix formation and the establishment of a homeostatic muscle niche are essential for maintaining muscle health, excessive accumulation of FAPs and their aberrant differentiation leads to the fibrofatty degeneration that is a hallmark of myopathies and muscular dystrophies. Recent advancements, including single-cell RNA sequencing and in vivo analysis of FAPs, are providing deeper insights into the functions and specialization of FAPs, shedding light on their roles in both health and disease. This review will explore the above insights, discussing how FAP dysregulation contributes to muscle diseases. It will offer a concise overview of potential therapeutic interventions targeting FAPs to restore disrupted interactions among FAPs and muscle-resident cells, ultimately addressing degenerative muscle loss in neuromuscular diseases.
    Keywords:  adipogenesis; fibroadipogenic; fibrosis; mesenchymal stem cells; muscle; muscular dystrophy; regeneration
    DOI:  https://doi.org/10.1177/22143602241298545
  12. Biochem Pharmacol. 2025 Feb 12. pii: S0006-2952(25)00061-9. [Epub ahead of print]234 116799
    Endoplasmic reticulum stress and unfolded protein response: Roles in skeletal muscle atrophy.
    Yanan Ji, Quan Jiang, Bingqian Chen, Xin Chen, Aihong Li, Dingding Shen, Yuntian Shen, Hua Liu, Xiaowei Qian, Xinlei Yao, Hualin Sun.
      Skeletal muscle atrophy is commonly present in various pathological states, posing a huge burden on society and patients. Increased protein hydrolysis, decreased protein synthesis, inflammatory response, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) are all important molecular mechanisms involved in the occurrence and development of skeletal muscle atrophy. The potential mechanisms of ERS and UPR in skeletal muscle atrophy are extremely complex and have not yet been fully elucidated. This article elucidates the molecular mechanisms of ERS and UPR, and discusses their effects on different types of muscle atrophy (muscle atrophy caused by disuse, cachexia, chronic kidney disease (CKD), diabetes mellitus (DM), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy (SBMA), aging, sarcopenia, obesity, and starvation), and explores the preventive and therapeutic strategies targeting ERS and UPR in skeletal muscle atrophy, including inhibitor therapy and drug therapy. This review aims to emphasize the importance of endoplasmic reticulum (ER) in maintaining skeletal muscle homeostasis, which helps us further understand the molecular mechanisms of skeletal muscle atrophy and provides new ideas and insights for the development of effective therapeutic drugs and preventive measures for skeletal muscle atrophy.
    Keywords:  ERS; Skeletal muscle atrophy; Therapy; UPR
    DOI:  https://doi.org/10.1016/j.bcp.2025.116799
  13. Nat Commun. 2025 Feb 19. 16(1): 1764
    Human skeletal muscle fiber heterogeneity beyond myosin heavy chains.
    Roger Moreno-Justicia, Thibaux Van der Stede, Ben Stocks, Jenni Laitila, Robert A Seaborne, Alexia Van de Loock, Eline Lievens, Diana Samodova, Leyre Marín-Arraiza, Oksana Dmytriyeva, Robin Browaeys, Kim Van Vossel, Lukas Moesgaard, Nurten Yigit, Jasper Anckaert, Anneleen Weyns, Ruud Van Thienen, Ronni E Sahl, Edmar Zanoteli, Michael W Lawlor, Michael Wierer, Pieter Mestdagh, Jo Vandesompele, Julien Ochala, Morten Hostrup, Wim Derave, Atul S Deshmukh.
      Skeletal muscle is a heterogenous tissue comprised primarily of myofibers, commonly classified into three fiber types in humans: one "slow" (type 1) and two "fast" (type 2A and type 2X). However, heterogeneity between and within traditional fiber types remains underexplored. We applied transcriptomic and proteomic workflows to 1050 and 1038 single myofibers from human vastus lateralis, respectively. Proteomics was conducted in males, while transcriptomics included ten males and two females. We identify metabolic, ribosomal, and cell junction proteins, in addition to myosin heavy chain isoforms, as sources of multi-dimensional variation between myofibers. Furthermore, whilst slow and fast fiber clusters are identified, our data suggests that type 2X fibers are not phenotypically distinct to other fast fibers. Moreover, myosin heavy chain-based classifications do not adequately describe the phenotype of myofibers in nemaline myopathy. Overall, our data indicates that myofiber heterogeneity is multi-dimensional with sources of variation beyond myosin heavy chain isoforms.
    DOI:  https://doi.org/10.1038/s41467-025-56896-6
  14. J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13715
    GDF15 Neutralization Ameliorates Muscle Atrophy and Exercise Intolerance in a Mouse Model of Mitochondrial Myopathy.
    Stephen E Flaherty, LouJin Song, Bina Albuquerque, Anthony Rinaldi, Mary Piper, Dinesh Hirenallur Shanthappa, Xian Chen, John Stansfield, Shoh Asano, Evanthia Pashos, Trenton Thomas Ross, Srinath Jagarlapudi, Abdul Sheikh, Bei Zhang, Zhidan Wu.
       BACKGROUND: Primary mitochondrial myopathies (PMMs) are disorders caused by mutations in genes encoding mitochondrial proteins and proteins involved in mitochondrial function. PMMs are characterized by loss of muscle mass and strength as well as impaired exercise capacity. Growth/Differentiation Factor 15 (GDF15) was reported to be highly elevated in PMMs and cancer cachexia. Previous studies have shown that GDF15 neutralization is effective in improving skeletal muscle mass and function in cancer cachexia. It remains to be determined if the inhibition of GDF15 could be beneficial for PMMs. The purpose of the present study is to assess whether treatment with a GDF15 neutralizing antibody can alleviate muscle atrophy and physical performance impairment in a mouse model of PMM.
    METHODS: The effects of GDF15 neutralization on PMM were assessed using PolgD257A/D257A (POLG) mice. These mice express a proofreading-deficient version of the mitochondrial DNA polymerase gamma, leading to an increased rate of mutations in mitochondrial DNA (mtDNA). These animals display increased circulating GDF15 levels, reduced muscle mass and function, exercise intolerance, and premature aging. Starting at 9 months of age, the mice were treated with an anti-GDF15 antibody (mAB2) once per week for 12 weeks. Body weight, food intake, body composition, and muscle mass were assessed. Muscle function and exercise capacity were evaluated using in vivo concentric max force stimulation assays, forced treadmill running and voluntary home-cage wheel running. Mechanistic investigations were performed via muscle histology, bulk transcriptomic analysis, RT-qPCR and western blotting.
    RESULTS: Anti-GDF15 antibody treatment ameliorated the metabolic phenotypes of the POLG animals, improving body weight (+13% ± 8%, p < 0.0001), lean mass (+13% ± 15%, p < 0.001) and muscle mass (+35% ± 24%, p < 0.001). Additionally, the treatment improved skeletal muscle max force production (+35% ± 43%, p < 0.001) and exercise performance, including treadmill (+40% ± 29%, p < 0.05) and voluntary wheel running (+320% ± 19%, p < 0.05). Mechanistically, the beneficial effects of GDF15 neutralization are linked to the reversal of the transcriptional dysregulation in genes involved in autophagy and proteasome signalling. The treatment also appears to dampen glucocorticoid signalling by suppressing circulating corticosterone levels in the POLG animals.
    CONCLUSIONS: Our findings highlight the potential of GDF15 neutralization with a monoclonal antibody as a therapeutic avenue to enhance physical performance and mitigate adverse clinical outcomes in patients with PMM.
    Keywords:  GDF15; antibody; mice; mitochondria; muscle; primary mitochondrial myopathy
    DOI:  https://doi.org/10.1002/jcsm.13715
  15. FASEB J. 2025 Feb 28. 39(4): e70409
    Muscle-specific ERRγ activation mitigates muscle atrophy after ACL injury.
    Aiping Lu, Katie J Sikes, Ping Guo, Matthieu Huard, Shelbi Green, Kelly Santangelo, Jacob Singer, Ashley Groesbeck, Scott Tashman, Vihang A Narkar, Johnny Huard.
      Anterior cruciate ligament (ACL) injury adversely affects skeletal muscle, leading to muscle atrophy and weakness, significantly impacting clinical outcomes. This study aimed to determine if estrogen-related receptor gamma (ERRγ) overexpression in skeletal muscle could mitigate muscle atrophy after ACL injury. An animal model with selective overexpression of ERRγ in skeletal muscle (ERR-gamma transgenic mice, TG) and WT control mice were used for this study. All the mice received a mechanical ACL rupture and were euthanized at 4- and 8-week post-injury. Muscle histology, atrophy, and function were evaluated and compared between the TG and WT mice. Muscle-specific ERRγ activation in TG mice demonstrated a reduction in muscle fiber atrophy, which consequently ameliorated muscle function loss post-ACL rupture. Less fibrogenic cellular expansion and muscle fibrosis were observed after ACL injury in TG mice compared to WT mice. Both male and female TG mice can maintain their muscle function 4 weeks after ACL rupture with the muscle function of female TG mice declining 8 weeks post-injury. In vivo results revealed that ERRγ activation decreased fibrogenic factors, P65, and myostatin expression, prevented the functional loss of muscle progenitor cells (MPCs), and increased CD31 and VEGF expression. These results suggest that overexpression ERRγ in skeletal muscle has a beneficial effect in preventing muscle atrophy and fibrosis after ACL rupture. This study's results will help to develop a novel rehabilitation approach that can significantly improve outcomes after ACL injury.
    Keywords:  ACL injury; ERRγ overexpression; muscle atrophy; vascularization
    DOI:  https://doi.org/10.1096/fj.202402021R
  16. ACS Biomater Sci Eng. 2025 Feb 20.
    Human iPSC-Derived Motor Neuron Innervation Enhances the Differentiation of Muscle Bundles Engineered with Benchtop Fabrication Techniques.
    Jeffrey W Santoso, Stephanie K Do, Riya Verma, Alexander V Do, Eric Hendricks, Justin K Ichida, Megan L McCain.
      Engineered skeletal muscle tissues are critical tools for disease modeling, drug screening, and regenerative medicine, but are limited by insufficient maturation. Because innervation is a critical regulator of skeletal muscle development and regeneration in vivo, motor neurons are hypothesized to improve the maturity of engineered skeletal muscle tissues. However, the impact of motor neurons on muscle phenotype when added prior to the onset of muscle differentiation is not clearly established. In this study, benchtop fabrication equipment was used to facilely fabricate chambers for engineering three-dimensional (3D) skeletal muscles bundles and measuring their contractile performance. Primary chick myoblasts were embedded in an extracellular matrix hydrogel solution and differentiated into engineered muscle bundles, with or without the addition of human induced pluripotent stem cell (hiPSC)-derived motor neurons. Muscle bundles differentiated with motor neurons had neurites distributed throughout their volume and a higher myogenic index compared to muscle bundles without motor neurons. Innervated muscle bundles also generated significantly higher twitch and tetanus forces in response to electrical field stimulation after 1 and 2 weeks of differentiation compared to noninnervated muscle bundles cultured with or without neurotrophic factors. Noninnervated muscle bundles also experienced a decline in rise and fall times as the culture progressed, whereas innervated muscle bundles and noninnervated muscle bundles with neurotrophic factors maintained more consistent rise and fall times. Innervated muscle bundles also expressed the highest levels of the genes for slow myosin light chain 3 (MYL3) and myoglobin (MB), which are associated with slow twitch fibers. These data suggest that motor neuron innervation enhances the structural and functional development of engineered skeletal muscle constructs and maintains them in a more oxidative phenotype.
    Keywords:  3D printing; PDMS; fast twitch; laser cutter; organ on chip; sarcomere; slow twitch
    DOI:  https://doi.org/10.1021/acsbiomaterials.4c02225
  17. Mol Ther Nucleic Acids. 2025 Mar 11. 36(1): 102451
    Decoding CKD-induced muscle atrophy through the critical role of lncRNA GAS5 and pyroptosis.
    Rong Huang, Xinying Tang, Shuang Liu, Lijing Sun.
      Skeletal muscle atrophy is a prevalent complication of chronic kidney disease (CKD) and serves as an indicator of adverse prognosis and poor quality of life; however, the underlying mechanisms remain ambiguous. Emerging evidence has shown that long non-coding RNAs (lncRNAs) are involved in the pathogenesis of skeletal muscle atrophy. Using RNA sequencing (RNA-seq), we discerned elevated GAS5 expression in the muscles of CKD mice and verified these findings by real-time qPCR. Transmission electron microscopy confirmed morphological signs of pyroptosis, a potentially causal cellular death form. Additionally, elevated levels of pyroptosis markers, such as NLRP3, cleaved caspase-1, and GSDMD-N, were observed in CKD mouse models and lipopolysaccharide (LPS)/ATP-stimulated C2C12 myotubes. Intriguingly, the knockdown of GAS5 reduced these markers, alleviating pyroptosis and enhancing myofiber size, both in vitro and in vivo. Furthermore, we pinpointed an interaction between GAS5 and the mitochondrial translation elongation factor (TUFM) through RNA pull-down and mass spectrometry. This interaction amplified NLRP3 activity, contributing to pyroptosis and muscle atrophy. Notably, overexpressing TUFM counterbalanced this effect. Fundamentally, the interaction between GAS5 and TUFM appears to compromise the anti-pyroptosis capacity of TUFM. Consequently, this amplifies the activation of the NLRP3 pathway, which may underpin the crucial mechanism driving pyroptosis-mediated muscle atrophy. Our findings provide new evidence for GAS5's role in regulating cellular pyroptosis in CKD-induced skeletal muscle atrophy.
    Keywords:  CKD; MT: Non-coding RNAs; NLRP3; chronic kidney disease; lncRNA; long non-coding RNA; pyroptosis; skeletal muscle atrophy
    DOI:  https://doi.org/10.1016/j.omtn.2025.102451
  18. Cell Death Dis. 2025 Feb 14. 16(1): 99
    Creatine transporter (SLC6A8) knockout mice exhibit reduced muscle performance, disrupted mitochondrial Ca2+ homeostasis, and severe muscle atrophy.
    Irene Pertici, Donato D'Angelo, Denis Vecellio Reane, Massimo Reconditi, Ilaria Morotti, Elena Putignano, Debora Napoli, Giorgia Rastelli, Gaia Gherardi, Agnese De Mario, Rosario Rizzuto, Simona Boncompagni, Laura Baroncelli, Marco Linari, Marco Caremani, Anna Raffaello.
      Creatine (Cr) is essential for cellular energy homeostasis, particularly in muscle and brain tissues. Creatine Transporter Deficiency (CTD), an X-linked disorder caused by mutations in the SLC6A8 gene, disrupts Cr transport, leading to intellectual disability, speech delay, autism, epilepsy, and various non-neurological symptoms. In addition to neurological alterations, Creatine Transporter knockout (CrT-/y) mice exhibit severe muscle atrophy and functional impairments. This study provides the first characterization of the skeletal muscle phenotype in CrT-/y mice, revealing profound ultrastructural abnormalities accompanied by reduced fiber cross-sectional area and muscle performance. Notably, mitochondria are involved, as evidenced by disrupted cristae, increased mitochondrial size, impaired Ca2+ uptake, reduced membrane potential and ATP production. Mechanistically, the expression of atrophy-specific E3 ubiquitin ligases and suppression of the IGF1-Akt/PKB pathway, regulated by mitochondrial Ca2+ levels, further support the atrophic phenotype. These findings highlight the profound impact of Cr deficiency on skeletal muscle, emphasizing the need for targeted therapeutic strategies to address both the neurological and peripheral manifestations of CTD. Understanding the underlying mechanisms, particularly mitochondrial dysfunction, could lead to novel interventions for this disorder.
    DOI:  https://doi.org/10.1038/s41419-025-07381-x
  19. Kidney Res Clin Pract. 2025 Feb 21.
    Protein-energy wasting in chronic kidney disease: mechanisms responsible for loss of muscle mass and function.
    S Russ Price, Xiaonan H Wang.
      The worldwide prevalence of chronic kidney disease (CKD) is high and growing, making CKD a leading cause of mortality. Skeletal muscle wasting, sometimes called sarcopenia or protein-energy wasting, is a frequent, serious consequence of CKD that reduces muscle strength and function, diminishes the quality of life of patients, and raises their risk of comorbidities and death. Muscle atrophy results from a disturbance in muscle protein balance that results from some combination of an increased rate of protein degradation, a decreased rate of protein synthesis, and dysfunctional muscle regeneration. Development of therapeutic strategies to ameliorate muscle loss, or maintain muscle mass, is challenging because of the multifactorial nature of the signals that alter protein homeostasis. This review discusses the cellular signals and mechanisms that negatively alter protein turnover in skeletal muscle during CKD.
    Keywords:  Atrophy; Kidney disease; Sarcopenia; Skeletal muscle
    DOI:  https://doi.org/10.23876/j.krcp.24.214
  20. Aging Cell. 2025 Feb 14. e70014
    Healthy Aging Metabolomic and Proteomic Signatures Across Multiple Physiological Compartments.
    R Moaddel, J Candia, C Ubaida-Mohien, T Tanaka, A Z Moore, M Zhu, G Fantoni, S Church, J D'Agostino, J Fan, N Shehadeh, S De, E Lehrmann, M Kaileh, E Simonsick, R Sen, J M Egan, L Ferrucci.
      The study of biomarkers in biofluids and tissues expanded our understanding of the biological processes that drive physiological and functional manifestations of aging. However, most of these studies were limited to examining one biological compartment, an approach that fails to recognize that aging pervasively affects the whole body. The simultaneous modeling of hundreds of metabolites and proteins across multiple compartments may provide a more detailed picture of healthy aging and point to differences between chronological and biological aging. Herein, we report proteomic analyses of plasma and urine collected in healthy men and women, age 22-92 years. Using these data, we developed a series of metabolomic and proteomic predictors of chronological age for plasma, urine, and skeletal muscle. We then defined a biological aging score, which measures the departure between an individual's predicted age and the expected predicted age for that individual based on the full cohort. We show that these predictors are significantly and independently related to clinical phenotypes important for aging, such as inflammation, iron deficiency anemia, muscle mass, and renal and hepatic functions. Despite a different set of selected biomarkers in each compartment, the different scores reflect a similar degree of deviation from healthy aging in single individuals, thus allowing identification of subjects with significant accelerated or decelerated biological aging.
    Keywords:  accelerated aging; aging; biological aging; elastic net; extracellular matrix; inflammation; mitochondrial health; plasma proteomics; senescence; urine proteomics
    DOI:  https://doi.org/10.1111/acel.70014
  21. J Physiol Biochem. 2025 Feb 19.
    The link between Mitochondria and Sarcopenia.
    Nurul Tihani Kamarulzaman, Suzana Makpol.
      Sarcopenia, a widespread condition, is characterized by a variety of factors influencing its development. The causes of sarcopenia differ depending on the age of the individual. It is defined as the combination of decreased muscle mass and impaired muscle function, primarily observed in association with ageing. As people age from 20 to 80 years old, there is an approximate 30% reduction in muscle mass and a 20% decline in cross-sectional area. This decline is attributed to a decrease in the size and number of muscle fibres. The regression of muscle mass and strength increases the risk of fractures, frailty, reduced quality of life, and loss of independence. Muscle cells, fibres, and tissues shrink, resulting in diminished muscle power, volume, and strength in major muscle groups. One prominent theory of cellular ageing posits a strong positive relationship between age and oxidative damage. Heightened oxidative stress leads to early-onset sarcopenia, characterized by neuromuscular innervation breakdown, muscle atrophy, and dysfunctional mitochondrial muscles. Ageing muscles generate more reactive oxygen species (ROS), and experience decreased oxygen consumption and ATP synthesis compared to younger muscles. Additionally, changes in mitochondrial protein interactions, cristae structure, and networks may contribute to ADP insensitivity, which ultimately leads to sarcopenia. Within this framework, this review provides a comprehensive summary of our current understanding of the role of mitochondria in sarcopenia and other muscle degenerative diseases, highlighting the crucial need for further research in these areas.
    Keywords:  Mitochondria; Mitochondrial protein interactions; Muscle ageing; Oxidative stress; Sarcopenia
    DOI:  https://doi.org/10.1007/s13105-024-01062-7
  22. FEBS Open Bio. 2025 Feb 17.
    Piezo1 channels enhance anabolic signaling activation induced by electrical stimulation of cultured myotubes.
    Natalia A Vilchinskaya, Ksenia V Sergeeva, Boris S Shenkman, Timur M Mirzoev.
      Mechanically activated (MA) Piezo1 channels play an important role in both normal physiology and pathological dysfunction in multiple tissues and organs. In skeletal muscle cells, Piezo1 channels are involved in the regulation of postnatal myogenesis and muscle regeneration after injury. To further understand the role of MA Piezo1 channels as potential critical sensors of mechanical perturbations during muscle contractions, we studied the possible contribution of MA Piezo1 channels to enhanced protein synthetic response of C2C12 myotubes to mechanical simulation. C2C12 myotubes were subjected to mechanical stimulation by electrical pulse stimulation (EPS) alone or EPS in combination with Yoda1, Gadolinium or Yoda1 + Gadolinium. EPS alone elicited an increase in anabolic signaling and protein synthesis (PS). Incubation with Yoda1 during EPS enhanced anabolic signaling and PS compared to EPS alone. Gadolinium or Yoda1 + gadolinium during EPS abolished or diminished the Yoda1 + EPS-induced effects on anabolic signaling and PS. Our work demonstrates that chemical activation of Piezo1 channels during mechanical stimulation contributes to enhanced protein anabolism in C2C12 myotubes.
    Keywords:  C2C12 myotubes; Piezo1; Yoda1; electrical pulse stimulation; gadolinium; protein synthesis
    DOI:  https://doi.org/10.1002/2211-5463.70008
  23. J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13740
    Low-Magnitude High-Frequency Vibration Attenuates Sarcopenia by Modulating Mitochondrial Quality Control via Inhibiting miR-378.
    Yu-Feng Long, Can Cui, Qianjin Wang, Zhen Xu, Simon Kwoon-Ho Chow, Ning Zhang, Ronald Man Yeung Wong, Elvis Chun-Sing Chui, Rebecca Schoenmehl, Christoph Brochhausen, Clinton Rubin, Gang Li, Ling Qin, Da-Zhi Yang, Wing-Hoi Cheung.
       BACKGROUND: Sarcopenia, the age-related decline in muscle mass and muscle strength, significantly contributes to falls, diminished quality of life, and mortality. Although mitochondrial dysfunction is increasingly implicated in sarcopenia, the underlying mechanisms are not fully discovered. Low-magnitude high-frequency vibration (LMHFV), a recommended treatment by the Centers for Disease Control and Prevention (CDC) to reduce fall risk, remains poorly understood of the mechanism on improving skeletal muscle quality. This study aims to investigate whether mitochondrial dysfunction contributes to sarcopenia and evaluate whether LMHFV mitigates sarcopenia by improving mitochondrial homeostasis.
    METHODS: The relationship between mitochondria dysfunction and sarcopenia using senescence accelerated mice prone 8 (SAMP8) model was investigated, assessing muscle and mitochondria. The effects of LMHFV on muscle and mitochondria were evaluated in SAMP8 mice during sarcopenia progression. The role of miR-378 in muscle and mitochondrial homeostasis were evaluated in SAMP8 mice and transgenic over-expressing miR-378 mice (TG mice). The target gene of miR-378 was investigated by dual-luciferase reporter assay in C2C12 cells. Subsequently, we evaluated the effect of LMHFV on miR-378 using both mouse models.
    RESULTS: Reduction in muscle strength was observed from the ages of month 8 to 10 in SAMP8 mice (grip strength decreased 27.1%, p = 0.0263; twitch force decreased 29.1%, p = 0.0178; tetanic force decreased 29.9%, p = 0.011), as well as muscle atrophy (cross-section area: 38.3%, p = 0.0121). Mitochondrial morphological deterioration was noticed from month 6 to 10. Mitochondrial homeostasis, including biogenesis, fusion, fission, mitophagy, and ATP production declined from month 6 to 10. Compared to control group at month 10, knocking down miR-378 in SAMP8 mice mitigated sarcopenia (twitch force increased 44.3%, p = 0.0023; tetanic force increased 51.9%, p = 0.0005), improved mitochondrial morphologies (mitochondrial number increased 1.65-fold, p = 0.0023; mitochondrial density increased 1.65-fold, p = 0.0023; mitochondrial relative area increased 9.05-fold, p = 0.0019) along with improved mitochondrial homeostasis. Over-expressing miR-378 in transgenic mice exacerbated muscle atrophy and mitochondrial deterioration significantly. The dual-luciferase reporter assay in C2C12 cells revealed that miR-378 inhibited PGC-1α directivity. LMHFV was found to mitigate sarcopenia by modulating mitochondrial homeostasis, such as attenuating mitochondrial morphological deterioration and improving mitochondrial biogenesis through increasing PGC-1α via inhibiting miR-378 in skeletal muscle.
    CONCLUSIONS: Our findings indicate that mitochondrial biogenesis, fusion, fission, and mitophagy were compromised during progression of sarcopenia, with mitochondrial deterioration preceding the onset of sarcopenia symptoms. The study also demonstrated that LMHFV could attenuate sarcopenia by modulating mitochondrial quality control through inhibiting miR-378, highlighting its therapeutic potential in the management of age-related muscular degeneration.
    Keywords:  miR‐378; mitochondria; sarcopenia; skeletal muscle; vibration
    DOI:  https://doi.org/10.1002/jcsm.13740
  24. Regen Ther. 2025 Mar;28 473-480
    PDZRN3 regulates adipogenesis of mesenchymal progenitors in muscle.
    Hiroki Iida, Minako Kawai-Takaishi, Yoshihiro Miyagawa, Yasuhiko Takegami, Akiyoshi Uezumi, Takeshi Honda, Shiro Imagama, Tohru Hosoyama.
       Introduction: Intramuscular adipose tissue (IMAT) is frequently formed in certain pathological conditions, such as biological aging, and ectopic fat accumulation leads to muscle weakness and a subsequent decline in physical function. Although mesenchymal progenitors (MPs) are present in postnatal skeletal muscle and are the cells from which IMAT originates, the molecular mechanism by which MPs contribute to IMAT formation has not been completely elucidated. Recently, we found that PDZ domain-containing ring finger 3 (PDZRN3), an E3-ubiquitin ligase, was highly expressed in MPs. In this study, we aimed to clarify the functions of PDZRN3 in MPs and the roles of PDZRN3 in IMAT formation using in vitro and in vivo experiments.
    Methods: Primary mouse MPs isolated from hindlimb muscles were applied to adipogenic differentiation conditions, and expression fluctuation of PDZRN3 was verified with adipogenic differentiation and Wnt signaling markers. The role of PDZRN3 on MP's adipogenesis was evaluated in vitro by gene knock-down experiments. To evaluate the contribution of PDZRN3 to IMAT formation in vivo, tamoxifen-inducible MP-specific Pdzrn3 knockout (Pdzrn3 MPcKO) mice were developed.
    Results: PDZRN3 was more expressed in MPs than in muscle stem cells, and its expression profile of PDZRN3 fluctuated with the adipogenic differentiation of MPs. Our results revealed that PDZRN3 suppressed the adipogenesis of MPs in vitro through the activation of Wnt signaling and that a decrease in PDZRN3 accelerated adipogenesis. Indeed, IMAT significantly increased in the denervated muscles of Pdzrn3 MPcKO mice.
    Conclusions: Our findings suggest that PDZRN3 is a key molecule in regulating IMAT formation. Since ectopic fat accumulation is frequently found in the skeletal muscles of older adults and also muscular dystrophy patients, PDZRN3 and its related pathways may represent a novel therapeutic target for these muscle pathologies.
    Keywords:  Intramuscular adipose tissue; Mesenchymal progenitor; PDZRN3; Wnt signaling
    DOI:  https://doi.org/10.1016/j.reth.2025.01.018
  25. J Exp Biol. 2025 Feb 17. pii: jeb.249966. [Epub ahead of print]
    Using physiologically-based models to predict in vivo skeletal muscle energetics.
    Ryan N Konno, Glen A Lichtwark, Taylor J M Dick.
      Understanding how muscles use energy is essential for elucidating the role of skeletal muscle in animal locomotion. Yet, experimental measures of in vivo muscle energetics are challenging to obtain, so physiologically-based muscle models are often used to estimate energy use. These predictions of individual muscle energy expenditure are not often compared to indirect whole-body measures of energetic cost. Here, we examined and illustrated the capability of physiologically-based muscle models to predict in vivo measures of energy use, which rely on fundamental relationships between muscle mechanical state and energy consumption. To improve model predictions and ensure a physiological basis for model parameters, we refined our model to include data from isolated muscle experiments and account for inefficiencies in ATP recovery processes. Simulations were performed to capture three different experimental protocols, which involved varying contraction frequency, duty cycle, and muscle fascicle length. Our results demonstrated the ability of the model to capture the dependence of energetic cost on mechanical state across contractile conditions, but tended to under predict the magnitude of energetic cost. Our analysis revealed that the model was most sensitive to the force-velocity parameters and the data informing the energetic parameters when predicting in vivo energetic rates. This work highlights it is the mechanics of skeletal muscle contraction that govern muscle energy use, although the precise physiological parameters for human muscle likely require detailed investigation.
    Keywords:  Biomechanics; Energetics; Mathematical modelling; skeletal muscle
    DOI:  https://doi.org/10.1242/jeb.249966
  26. Cell Mol Life Sci. 2025 Feb 21. 82(1): 81
    FOXO regulation of TXNIP induces ferroptosis in satellite cells by inhibiting glutathione metabolism, promoting Sarcopenia.
    Yasenjiang Maimaiti, Mukedasi Abulitifu, Zulifeiya Ajimu, Ting Su, Zhanying Zhang, Zhichao Yu, Hong Xu.
      Aging-related sarcopenia represents a significant health concern due to its impact on the quality of life in the elderly. This study elucidates the molecular mechanisms underlying sarcopenia by employing single-cell sequencing and public transcriptome databases to compare young and aged mouse skeletal muscles. Cellular classification and pseudotime analyses differentiated cell types and their interrelationships, revealing a marked reduction in satellite cell numbers and a consistent upregulation of TXNIP (Thioredoxin interacting protein) across various muscle cell populations in aged mice. Further transcriptomic data integration and batch correction from the GEO (Gene Expression Omnibus) database highlighted key differentially expressed genes. The role of TXNIP and its transcriptional regulation by FOXO1 (Forkhead box O1) was confirmed through in vitro experiments, which demonstrated FOXO1's influence on TXNIP expression and its subsequent suppression of glutathione metabolism, leading to satellite cell ferroptosis. Additionally, in vivo studies showed that overexpression of TXNIP in young mice's muscle tissues significantly reduced muscle mass, suggesting its potential role in the initiation of sarcopenia. Our findings suggest that FOXO1-mediated regulation of TXNIP and the disruption of glutathione metabolism are central to the process of sarcopenia, offering new insights into its pathogenesis.
    Keywords:  FOXO1; Ferroptosis; Muscle satellite cells; Sarcopenia; Single-cell sequencing; TXNIP
    DOI:  https://doi.org/10.1007/s00018-025-05592-1
  27. Mol Cell Biochem. 2025 Feb 21.
    Irisin: muscle's novel player in endoplasmic reticulum stress and disease.
    Joel Rimson Pinto, K Deepika Bhat, Bipasha Bose, P Sudheer Shenoy.
      Irisin, an exercise-induced myokine, exhibits elevated levels during physical activity, yet its role in modulating the unfolded protein response (UPR) remains poorly understood. This comprehensive review pioneers an in-depth examination of irisin-mediated endoplasmic reticulum (ER) stress mitigation across various diseases. We provide a nuanced characterization of irisin's molecular profile, biological activity, and significance as a skeletal muscle-derived cytokine analogue. Our discussion elucidates the complex interplay between exercise, irisin signalling, and metabolic outcomes, highlighting key molecular interactions driving salutary effects. Moreover, we delineate the UPR's role as a critical ER stress countermeasure and underscore irisin's pivotal function in alleviating this stress, revealing potential therapeutic avenues for disease management. Exercise-induced release of irisin ameliorates ER stress through AMPK phosphorylation during various diseases (Icon image source: www.flaticon.com ).
    Keywords:  Atrophied muscle; ER stress; Healthy muscle; Irisin; Myokine; Skeletal muscle
    DOI:  https://doi.org/10.1007/s11010-025-05225-y
  28. J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13711
    HMGB1 in Septic Muscle Atrophy: Roles and Therapeutic Potential for Muscle Atrophy and Regeneration.
    Si-Yuan Qi, Qiqi Wu, Peng-Hui Xiang, Chao-Yao Hou, Zhaofeng Kang, Meng-Qi Chen, Chengla Yi, Xiangjun Bai, Tianyu Li, Zhanfei Li, Wei-Ming Xie.
      Currently, the treatment of septic myopathy presents significant challenges with implications for increased mortality rates and prolonged hospitalizations. Effective therapeutic strategies for septic myopathy remain elusive, highlighting an urgent need for novel therapeutic approaches. High-mobility group box 1 (HMGB1) is a conserved nonhistone nuclear protein that is released passively from deceased cells or actively secreted by activated immune cells, influencing both infectious and noninfectious inflammatory responses. Studies have indicated that HMGB1 likely plays a pivotal role in the pathogenesis of septic myopathy by crucial pathways associated with muscle atrophy and contributing to muscle regeneration under certain conditions. This review aims to summarize the possible mechanisms of HMGB1 in muscle atrophy and its potential in muscle regeneration, providing a theoretical basis for HMGB1 treatment of septic myopathy. Research shows that the dual role of HMGB1 is related to its specific forms, which are influenced to varying degrees by environmental factors. HMGB1 is a key participant in septic muscle atrophy, whereas HMGB1 shows therapeutic potential in muscle regeneration. One key mechanism by which HMGB1 contributes to septic muscle atrophy is through the exacerbation of inflammation. HMGB1 can amplify the inflammatory response by promoting the release of pro-inflammatory cytokines, which further damages muscle tissue. HMGB1 is also involved in promoting cell death in sepsis, which contributes to muscle degradation. Another important mechanism is the regulation of protein degradation systems. HMGB1 can activate the ubiquitin-proteasome system and autophagy-lysosome pathway, both of which are crucial for the breakdown of muscle proteins during atrophy. Conversely, targeting HMGB1 has shown the potential to ameliorate muscle atrophy in various diseases. For instance, HMGB1 has been shown to promote muscle vascular regeneration, modify stem cell status and enhance stem cell migration and differentiation, all of which are beneficial for muscle repair and recovery. Pharmacological inhibition of HMGB1 has been explored, with several drugs demonstrating efficacy in reducing inflammation and muscle degradation in sepsis models. These findings suggest that HMGB1 inhibition could be a viable therapeutic approach for septic myopathy. However, the function of promoting muscle regeneration in septic myopathy needs further research. HMGB1 emerges as a promising therapeutic target for the treatment of muscle atrophy in sepsis. This review focuses on identifying the correlation between HMGB1 and septic myopathy, analysing the possible role of HMGB1 in disease development and examining the feasibility of HMGB1 as a therapeutic target.
    Keywords:  HMGB1; clinical therapy; muscle atrophy; sepsis; tissue regeneration
    DOI:  https://doi.org/10.1002/jcsm.13711
  29. bioRxiv. 2025 Jan 27. pii: 2025.01.24.634796. [Epub ahead of print]
    Epigenetic small molecule screening identifies a new HDACi compound for ameliorating Duchenne muscular dystrophy.
    Ke'ale W Louie, Eva H Hasegawa, Gist H Farr, Amanda Ignacz, Alison Paguio, Alyssa Maenza, Alison G Paquette, Clarissa Henry, Lisa Maves.
      Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease. There are currently few effective therapies to treat the disease, although many approaches are being pursued. Certain histone deacetylase inhibitors (HDACi) have been shown to ameliorate DMD phenotypes in mouse and zebrafish animal models, and the HDACi givinostat has recently gained FDA approval for DMD. Our goal was to identify additional HDACi, or other classes of epigenetic small molecules, that are beneficial for DMD. Using an established animal model for DMD, the zebrafish dmd mutant strain sapje , we screened a library of over 800 epigenetic small molecules of various classes. We used a quantitative muscle birefringence assay to assess and compare the effects of these small molecule treatments on dmd mutant zebrafish skeletal muscle. Our screening identified a new HDACi, SR-4370, that ameliorated dmd mutant zebrafish skeletal muscle degeneration, in addition to HDACi previously shown to improve dmd zebrafish. We find that a single early treatment of HDACi can ameliorate dmd zebrafish. Furthermore, we find that HDACi that improve dmd muscle also cause increased histone acetylation in zebrafish larvae, whereas givinostat does not appear to increase histone acetylation or improve zebrafish dmd muscle. Our results add to the growing evidence that HDACi are promising candidates for treating DMD. Our study also provides further support for the effectiveness of small-molecule screening in dmd zebrafish.
    Graphical abstract:
    DOI:  https://doi.org/10.1101/2025.01.24.634796
  30. J Lipid Res. 2025 Feb 12. pii: S0022-2275(25)00016-1. [Epub ahead of print] 100756
    PI3KC2β depletion rescues endosomal trafficking defects in Mtm1 knockout skeletal muscle cells.
    Mélanie Mansat, Afi Oportune Kpotor, Anne Mazars, Gaëtan Chicanne, Bernard Payrastre, Julien Viaud.
      Phosphoinositides constitute a class of seven phospholipids found in cell membranes, regulating various cellular processes like trafficking and signaling. Mutations in their metabolizing enzymes are implicated in several pathologies, including X-Linked Myotubular Myopathy (XLMTM), a severe myopathy caused by mutations in the MTM1 gene. MTM1 acts as a phosphoinositide 3-phosphatase, targeting PI3P and PI(3,5)P2, crucial for endolysosomal trafficking. Studies in XLMTM animal models have demonstrated that loss of MTM1 results in PI3P accumulation in muscle. Moreover, inactivating the class II phosphoinositide 3-kinase beta (PI3KC2β) rescues the pathological phenotype and decreases PI3P levels, suggesting that the normalization of PI3P levels could be responsible for that rescue mechanism. In this study, using an Mtm1 knockout skeletal muscle cell line, we investigated the localization of the PI3P pool metabolized by MTM1 in endosomal compartments. Our findings reveal that MTM1 metabolizes a pool of PI3P on EEA1-positive endosomes, leading to impaired Rab4 recycling vesicle biogenesis in the absence of MTM1. Furthermore, depletion of PI3KC2β rescued Mtm1 knockout cell phenotype, normalized PI3P level on EEA1-positive endosomes, and restored Rab4-positive vesicle biogenesis. These results indicate that MTM1 is critical for the homeostasis of endosomal trafficking, and that depletion of MTM1 potentially alters cargo recycling through Rab4-positive vesicles trafficking.
    Keywords:  Cell signaling; Muscle; Phosphoinositide; Phospholipids/Trafficking
    DOI:  https://doi.org/10.1016/j.jlr.2025.100756
  31. Free Radic Biol Med. 2025 Feb 14. pii: S0891-5849(25)00090-5. [Epub ahead of print]
    Deuterium-reinforced polyunsaturated fatty acids protect against muscle atrophy by STZ-induced diabetic mice.
    Hiroaki Eshima, Ishihara Tomoaki, Ayaka Tabuchi, Yutaka Kano, Kenji Kurokawa, Mikhail S Shchepinov.
      Oxidative stress and reactive oxygen species (ROS) have been linked to muscle atrophy and weakness. Diabetes increases the oxidative status in all tissues, including muscle tissues, but the role of lipid ROS on diabetes-induced muscle atrophy is not fully understood. Deuterium reinforced polyunsaturated fatty acids (D-PUFA) are more resistant to ROS-initiated chain reaction of lipid peroxidation than regular hydrogenated PUFA (H-PUFA). In this study, we tested the hypothesis that D-PUFA would protect muscle atrophy induced by diabetes driven by an accumulation of lipid hydroperoxides (LOOH). C57BL/6J mice were dosed with H-PUFA or D-PUFA for four weeks through dietary supplementation (10 mg/day) and then injected with streptozotocin (STZ) to induce insulin-deficient diabetes. After two weeks, muscles tissues were analyzed for individual muscle mass, force generating capacity and cross-sectional area. Skeletal muscle fibers from diabetic mice exhibited increased total ROS and LOOH. This was abolished by the D-PUFA supplementation regardless of accumulated iron. D-PUFA were found to be protective against muscle atrophy and weakness from STZ-induced diabetes. Prevention of muscle atrophy and weakness by D-PUFA might be independent of ACSL4/LPCAT3/15-LOX pathway. These findings provide novel insights into the role of LOOH in the mechanistic link between oxidative stress and diabetic myopathy and suggest a novel therapeutic approach to diabetes-associated muscle weakness.
    Keywords:  D-PUFA; Diabetes; Lipid hydroperoxides; Oxidative stress; Polyunsaturated fatty acids; Reactive oxygen species; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.02.015
  32. Alzheimers Dement (N Y). 2025 Jan-Mar;11(1):11(1): e70056
    Exercise intensity matters: A review on evaluating the effects of aerobic exercise intensity on muscle-derived neuroprotective myokines.
    Navabeh Zare, David J Bishop, Itamar Levinger, Mark A Febbraio, James R Broatch.
      Exercise as a medical intervention is effective to help prevent and manage many chronic and complex diseases, including dementia. There is evidence to suggest that regular aerobic exercise protects against age-related brain atrophy and reduces the risk of cognitive decline. The mechanisms by which exercise infers a neuroprotective effect remain to be established but may be related to a maintenance of brain volume and neuronal survival, improved cerebrovascular density and function, and/or increased synaptic plasticity. In addition, there is growing evidence to suggest the beneficial effects of exercise on brain health and cognitive function are, at least in part, mediated by factors released by skeletal muscle during contraction. The fact that the brain responds to exercise suggests that muscle-derived peripheral factors, or "myokines," may play a key role in muscle-brain crosstalk and exercise neuroprotection. However, the most effective "dose" of aerobic exercise to promote beneficial changes in these myokine pathways is currently unknown. Specifically, most of the evidence to date is from studies that have used moderate-intensity exercise, and research investigating the merit of high-intensity exercise is scarce. Considering the well-established role of high-intensity interval training in protecting against numerous medical conditions, more research is needed to identify the most effective "dose" of exercise to improve the beneficial effects of these myokines.
    Highlights: Neuroprotection through exercise: Regular aerobic exercise mitigates age-related brain atrophy and cognitive decline via multiple mechanisms, including brain volume maintenance, improved cerebrovascular function, and synaptic plasticity. Myokines as mediators: Muscle-derived factors (myokines) play a crucial role in muscle-brain crosstalk, significantly contributing to the neuroprotective effects of exercise. Intensity matters: The review underscores the necessity to define and study exercise intensity, revealing high-intensity exercise may be as effective, if not more, in promoting neuroprotective myokine levels compared to moderate-intensity exercise. Future research directions: This review emphasizes the need for well-controlled studies to explore the optimal exercise dose for enhancing myokine pathways and their implications for neurodegenerative disease prevention.
    Keywords:  dementia; exercise intensity; high‐intensity exercise training; moderate‐intensity exercise training; myokines; neuroprotection
    DOI:  https://doi.org/10.1002/trc2.70056
  33. Clin Transl Med. 2025 Feb;15(2): e70227
    Muscle-specific gene editing improves molecular and phenotypic defects in a mouse model of myotonic dystrophy type 1.
    Mariapaola Izzo, Jonathan Battistini, Elisabetta Golini, Christine Voellenkle, Claudia Provenzano, Tiziana Orsini, Georgios Strimpakos, Ferdinando Scavizzi, Marcello Raspa, Denisa Baci, Svetlana Frolova, Spyros Tastsoglou, Germana Zaccagnini, Jose Manuel Garcia-Manteiga, Genevieve Gourdon, Silvia Mandillo, Beatrice Cardinali, Fabio Martelli, Germana Falcone.
       BACKGROUND: Myotonic dystrophy type 1 (DM1) is a genetic multisystemic disease, characterised by pleiotropic symptoms that exhibit notable variability in severity, nature and age of onset. The genetic cause of DM1 is the expansion of unstable CTG-repeats in the 3' untranslated region (UTR) of the DMPK gene, resulting in the accumulation of toxic CUG-transcripts that sequester RNA-binding proteins and form nuclear foci in DM1 affected tissues and, consequently, alter various cellular processes. Therapeutic gene editing for treatment of monogenic diseases is a powerful technology that could in principle remove definitively the disease-causing genetic defect. The precision and efficiency of the molecular mechanisms are still under investigation in view of a possible use in clinical practice.
    METHODS: Here, we describe the application of the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) strategy to remove the CTG-expansion in the DMPK gene in a mouse model carrying the human transgene from a DM1 patient. To optimise the editing efficiency in vivo, we identified new tools that allowed to improve the expression levels and the activity of the CRISPR/Cas9 machinery. Newly designed guide RNA pairs were tested in DM1-patient derived cells before in vivo application. Edited cells were analysed to assess the occurrence of off-target and the accuracy of on-target genomic events. Gene editing-dependent and -independent mechanisms leading to decreased accumulation of the mutated DMPK transcripts were also evaluated.
    RESULTS AND CONCLUSION: Systemic delivery of CRISPR/Cas9 components in DM1 mice, through myotropic adeno-associated viral vectors, led to significant improvement of molecular alterations in the heart and skeletal muscle. Importantly, a persistent increase of body weight, improvement of muscle strength and body composition parameters were observed in treated animals. Accurate evaluation of CRISPR/Cas9-mediated-phenotypic recovery in vivo is a crucial preclinical step for the development of a gene therapy for DM1 patients.
    KEY POINTS: In vivo application of a therapeutic gene editing strategy for permanent deletion of the pathogenetic CTG-repeat amplification in the DMPK gene that causes myotonic dystrophy type 1. Following treatment, diseased mice show a significant improvement of both molecular and phenotypic defects.
    Keywords:  CRISPR/Cas9; CTG repeats; DM1; DMPK; DMSXL mouse model; MyoAAV; gene editing; muscle; myotonic dystrophy type 1
    DOI:  https://doi.org/10.1002/ctm2.70227
  34. Cell Metab. 2025 Feb 11. pii: S1550-4131(25)00024-5. [Epub ahead of print]
    Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST.
    Hans-Georg Sprenger, Melanie J Mittenbühler, Yizhi Sun, Jonathan G Van Vranken, Sebastian Schindler, Abhilash Jayaraj, Sumeet A Khetarpal, Amanda L Smythers, Ariana Vargas-Castillo, Anna M Puszynska, Jessica B Spinelli, Andrea Armani, Tenzin Kunchok, Birgitta Ryback, Hyuk-Soo Seo, Kijun Song, Luke Sebastian, Coby O'Young, Chelsea Braithwaite, Sirano Dhe-Paganon, Nils Burger, Evanna L Mills, Steven P Gygi, Joao A Paulo, Haribabu Arthanari, Edward T Chouchani, David M Sabatini, Bruce M Spiegelman.
      Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive. Here, we use a systematic approach to identify how mitochondria remodel their metabolome in response to exercise training. From these data, we find that EGT accumulates in muscle mitochondria upon exercise training. Proteome-wide thermal stability studies identify 3-mercaptopyruvate sulfurtransferase (MPST) as a direct molecular target of EGT; EGT binds to and activates MPST, thereby boosting mitochondrial respiration and exercise training performance in mice. Together, these data identify the first physiologically relevant EGT target and establish the EGT-MPST axis as a molecular mechanism for regulating mitochondrial function and exercise performance.
    Keywords:  MPST; ergothioneine; exercise; mitochondria
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.024
This page is being maintained by Thomas Krichel. It was last updated on 2025‒02‒23 at 2:06.