bims-moremu 2025-05-18 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–05–18
thirty papers selected by
Anna Vainshtein, Craft Science Inc.

Identification of a resistance-exercise-specific signalling pathway that drives skeletal muscle growth.
Exercise Attenuates Skeletal Muscle Atrophy in Senescent SAMP8 Mice: Metabolic Insights from NMR-Based Metabolomics.
Cancer-induced FOXP1 disrupts and reprograms skeletal-muscle circadian transcription in cachexia.
Muscle wasting and the response to exercise in lung-injured mice is not primarily driven through the glucocorticoid axis.
Nuclear Deformities Minimally Affect Fiber-Type-Specific Disease Progression in Murine Models of Nuclear Envelope Myopathy.
Estrogen-related receptors regulate innate and adaptive muscle mitochondrial energetics through cooperative and distinct actions.
Iron Metabolism and Muscle Aging: Where Ferritinophagy Meets Mitochondrial Quality Control.
GsMTx4-blocked PIEZO1 channel promotes myogenic differentiation and alleviates myofiber damage in Duchenne muscular dystrophy.
Fatigue Resistance and Mitochondrial Adaptations to Isometric Interval Training in Dystrophin-Deficient Muscle: Role of Contractile Load.
Neuromuscular junction transcriptome analysis of spinal and bulbar muscular atrophy mice implicates sarcomere gene expression and calcium flux dysregulation in disease pathogenesis.
Analysis of the mechanism of skeletal muscle atrophy from the pathway of decreased protein synthesis.
Harmonizing WHO-ICOPE with muscle health to promote healthy longevity.
Muscle-specific kinase levels in blood are an early diagnostic biomarker for SOD1-93A mouse model of ALS.
Site-specific quantification of the in vivo UFMylome reveals myosin modification in ALS.
ErbB2 as a therapeutic target for post-trauma muscle recovery.
Modeling Idiopathic Inflammatory Myopathy in the Bioinspired Muscle Tissue on Chip.
The contribution of age and sex hormones to female neuromuscular function across the adult lifespan.
Identification of differentially expressed genes in resting human skeletal muscle of sedentary versus strength and endurance- trained individuals using bioinformatics analysis and in vitro validation.
Microdroplet-Engineered Skeletal Muscle Organoids from Primary Tissue Recapitulate Parental Physiology with High Reproducibility.
A combined experimental and computational analysis of mantATP turnover in skinned muscle fibers.
Luteolin Induces Nrf2 Activity in C2C12 Cells: Implications for Muscle Health.
Recent insights into limb-girdle muscular dystrophy: Impacts, therapy, and challenges.
Development of Immunochemical Systems for Detection of Human Skeletal Troponin I Isoforms.
Mechanically sensitive MAPK signalling mediates resistance exercise-induced muscle growth.
Adverse effects of high-fat diet consumption on contractile mechanics of isolated mouse skeletal muscle are reduced when supplemented with resveratrol.
Cisd1 synergizes with Cisd2 to modulate protein processing by maintaining mitochondrial and ER homeostasis.
Enhancement of Energy Metabolism in Skeletal Myocytes Protects Against Age-Related Sarcopenia.
Unacylated Ghrelin Counteracts Contractile and Mitochondrial Dysfunction in Cancer Cachexia.
GDF8 and activin A blockade protects against GLP-1-induced muscle loss while enhancing fat loss in obese male mice and non-human primates.
Towards Precision in Sarcopenia Assessment: The Challenges of Multimodal Data Analysis in the Era of AI.

Nat Metab. 2025 May 15.

Identification of a resistance-exercise-specific signalling pathway that drives skeletal muscle growth.

Wenyuan G Zhu, Aaron C Q Thomas, Gary M Wilson, Chris McGlory, Jamie E Hibbert, Corey Gk Flynn, Ramy K A Sayed, Hector G Paez, Marius Meinhold, Kent W Jorgenson, Jae-Sung You, Nathaniel D Steinert, Kuan-Hung Lin, Martin J MacInnis, Joshua J Coon, Stuart M Phillips, Troy A Hornberger.

Endurance and resistance exercise lead to distinct functional adaptations: the former increases aerobic capacity and the latter increases muscle mass. However, the signalling pathways that drive these adaptations are not well understood. Here we identify phosphorylation events that are differentially regulated by endurance and resistance exercise. Using a model of unilateral exercise in male participants and deep phosphoproteomic analyses, we find that a prolonged activation of a signalling pathway involving MKK3b/6, p38, MK2 and mTORC1 occurs specifically in response to resistance exercise. Follow-up studies in both male and female participants reveal that the resistance-exercise-induced activation of MKK3b is highly correlated with the induction of protein synthesis (R = 0.87). Additionally, we show that in mice, genetic activation of MKK3b is sufficient to induce signalling through p38, MK2 and mTORC1, along with an increase in protein synthesis and muscle fibre size. Overall, we identify core components of a signalling pathway that drives the growth-promoting effects of resistance exercise.

DOI: https://doi.org/10.1038/s42255-025-01298-7
Molecules. 2025 Apr 30. pii: 2003. [Epub ahead of print]30(9):

Exercise Attenuates Skeletal Muscle Atrophy in Senescent SAMP8 Mice: Metabolic Insights from NMR-Based Metabolomics.

Wenfang Wu, Linglin Zhang, Yifen Chen, Caihua Huang, Longhe Yang, Donghai Lin.

  Age-related skeletal muscle atrophy is a major health concern in the elderly, contributing to reduced mobility, increased risk of falls, and metabolic dysfunction. The senescence-accelerated prone 8 (SAMP8) mouse model, known for its rapid aging and early cognitive decline, serves as an essential model for studying age-related muscle degeneration. While previous studies have shown that exercise attenuates muscle atrophy by promoting regeneration and improving strength, the underlying metabolic mechanisms remain poorly understood. This study used the SAMP8 model to evaluate the effects of exercise on muscle atrophy and associated metabolic changes. Our results show that exercise promoted muscle growth by reducing body weight, increasing skeletal muscle mass, and decreasing fat accumulation. Furthermore, exercise improved grip strength, muscle tone, and muscle fiber cross-sectional area, thereby preserving muscle functionality. NMR-based metabolomic analysis identified key metabolic pathways modulated by exercise, including glycine, serine, and threonine metabolism; alanine, aspartate, and glutamate metabolism; pyruvate metabolism; and taurine and hypotaurine metabolism. These findings underscore the therapeutic potential of exercise in combating age-related muscle wasting and elucidate the metabolic pathways underlying its benefits.

Keywords:  NMR-based metabolomics; SAMP8; aging; exercise; skeletal muscle

DOI:  https://doi.org/10.3390/molecules30092003
Cell Rep. 2025 May 10. pii: S2211-1247(25)00460-7. [Epub ahead of print]44(5): 115689

Cancer-induced FOXP1 disrupts and reprograms skeletal-muscle circadian transcription in cachexia.

Jeremy B Ducharme, Daria Neyroud, Martin M Schonk, Miguel A Gutierrez-Monreal, Zhiguang Huo, Haley O Tucker, Karyn A Esser, Sarah M Judge, Andrew R Judge.

  Cancer cachexia is a debilitating metabolic disorder characterized by involuntary loss of body and muscle mass, leading to increased morbidity and mortality. We previously found that forkhead box P1 (FoxP1) upregulation in skeletal muscle causes muscle wasting and is required for muscle wasting in response to cancer. However, transcriptional networks targeted by FoxP1 in skeletal muscles undergoing cancer-induced wasting remain largely unknown. Here, we identify FoxP1 as a key disruptor of the skeletal-muscle clock in response to cancer that reprograms circadian patterns of gene expression at cachexia onset. Specifically, we show that cancer-induced FoxP1 rewires the skeletal-muscle circadian transcriptome toward pathways associated with muscle wasting and disrupts the temporal patterning of pathways governing glucose, lipid, and oxidative metabolism. These findings thus implicate cancer/disease-specific functions of FOXP1 in the disruption and reprograming of the skeletal-muscle circadian transcriptome, which may contribute to muscle wasting and the development of cachexia.

Keywords:  CP: Cancer; ChIP-seq; RNA-seq; cancer cachexia; circadian rhythm; inflammation; metabolism; muscle atrophy; muscle clock; pancreatic cancer; skeletal muscle

DOI:  https://doi.org/10.1016/j.celrep.2025.115689
Am J Physiol Endocrinol Metab. 2025 May 13.

Muscle wasting and the response to exercise in lung-injured mice is not primarily driven through the glucocorticoid axis.

Chai-Chi Chuang Key, Lanazha Belfield, Jennifer Krall, Kevin Gibbs, Chun Liu, Lina Purcell, Renee D Stapleton, Matthew E Poynter, Michael J Toth, Matthew Quinn, Swapan K Das, D Clark Files.

  Background: Muscle wasting is common in patients with acute respiratory distress syndrome (ARDS). We have previously shown that acute lung-injured (ALI) mice develop muscle atrophy driven by muscle E3 ubiquitin ligase muscle RING-finger protein 1 (MuRF1). The muscle atrophy response in ALI mice can be partially alleviated by short durations of moderate-intensity treadmill exercise through unclear mechanisms. Glucocorticoid receptor (GR) signaling has been implicated in muscle wasting and repair, and the MuRF1 promoter contains a glucocorticoid response element. We examined the contribution of muscle GR signaling in ALI-associated muscle wasting and the response to exercise. Methods: Intratracheal lipopolysaccharides were instilled into wild type (WT) mice. Mice exercised for prescribed intensity and duration on a treadmill. GR knockdown was achieved through pharmacologic inhibition and the use of muscle specific GR knockout mice. Muscle structure and function was evaluated using physiologic and histochemical techniques and GR activation was assessed under multiple conditions. Results: Muscle wasting in ALI mice was associated with a GR transcriptional response which was suppressed by exercise. However, neither pharmacological inhibition of muscle GR signaling, nor genetic deletion of muscle GR prevented skeletal muscle wasting or recapitulated the benefits of exercise in WT ALI mice. Moreover, RNAseq of tibialis anterior and diaphragm skeletal muscle in WT mice revealed that exercise influenced genes related to skeletal muscle tissue remodeling, but pathway analysis suggested that this was unrelated to the glucocorticoid axis. Conclusion: GR signaling is dispensable for both ALI muscle wasting and its partial mitigation by exercise in mice.

Keywords:  Acute Respiratory Distress Syndrome; Early mobility; Exercise; Glucocorticoid axis; Skeletal muscle

DOI:  https://doi.org/10.1152/ajpendo.00039.2025
FASEB J. 2025 May 15. 39(9): e70615

Nuclear Deformities Minimally Affect Fiber-Type-Specific Disease Progression in Murine Models of Nuclear Envelope Myopathy.

Eiji Wada, Nao Susumu, Yukiko K Hayashi.

  Abnormalities in nuclear morphology are specific features of the nuclear envelopathies, including Emery-Dreifuss muscular dystrophy (EDMD). The presence of abnormally shaped nuclei in the skeletal muscles of EDMD patients and murine models has been reported both in vivo and in vitro; however, how the presence of nuclear architectural abnormalities affects disease development and progression remains unclear. In this study, we analyzed slow-twitch soleus (SOL) muscles and fast-twitch extensor digitorum longus (EDL) muscles from the following EDMD model mice: emerin knockout (Emd), LmnaH222P/H222P knockin (H222P), and Emd/H222P double-mutated (EH), to elucidate the effects of altered nuclear shapes on fiber-type-specific disease development. Dystrophic phenotypes were exclusively detected in the SOL muscles of EH mice, and myonuclear shape irregularities were observed only in the SOL muscle but not in the EDL muscle. Recovery from cardiotoxin (CTX) injection improved the shapes of peripheral myonuclei, and muscle histology and function, concomitant with an increase in the number and size of type 1 fibers in the regenerated SOL muscles of EH mice 42 days after the muscle damage. Importantly, nuclear morphology was relatively retained even after 126 days from the CTX injection, although dystrophic pathology gradually progressed. Taken together, our results indicate that the presence of nuclear morphological changes plays a minor role in the fiber-type-specific progression of muscular dystrophy in EDMD.

Keywords:  Emery‐Dreifuss muscular dystrophy; emerin; lamin A/C; muscle fiber type; muscle regeneration; nuclear shape

DOI:  https://doi.org/10.1096/fj.202500288R
Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2426179122

Estrogen-related receptors regulate innate and adaptive muscle mitochondrial energetics through cooperative and distinct actions.

Weiwei Fan, Tae Gyu Oh, Hui J Wang, Lillian Crossley, Mingxiao He, Hunter Robbins, Chandra Koopari, Yang Dai, Morgan L Truitt, Christopher Liddle, Ruth T Yu, Annette R Atkins, Michael Downes, Ronald M Evans.

  Mitochondrial energy metabolism is vital for muscle function and is tightly controlled at the transcriptional level, both in the basal state and during adaptive muscle remodeling. The importance of the transcription factors estrogen-related receptors (ERRs) in controlling innate mitochondrial energetics has been recently demonstrated. However, whether different ERR isoforms display distinct functions in glycolytic versus oxidative myofibers is largely unknown. Moreover, their roles in regulating exercise-induced adaptive mitochondrial biogenesis remain unclear. Using muscle-specific single and combinatorial knockout mouse models, we have identified both cooperative and distinct roles of the ERR isoforms ERRα and ERRγ in regulating mitochondrial energy metabolism in different muscles. We demonstrate the essential roles of both these ERRs in mediating adaptive mitochondrial biogenesis in response to exercise training. We further show that PGC1α-induced mitochondrial biogenesis is completely abolished in primary myotubes with ERRα deletion but not ERRγ, highlighting distinct roles of these two isoforms in adaptive mitochondrial remodeling. Mechanistically, we find that both ERRs directly bind to the majority of mitochondrial energetic genes and control their expression, largely through collaborative binding to the same genomic loci. Collectively, our findings reveal critical and direct regulatory roles of ERRα and ERRγ in governing both innate and adaptive mitochondrial energetics in skeletal muscle.

Keywords:  PGC1; energy metabolism; estrogen-related receptor; mitochondria; muscle

DOI:  https://doi.org/10.1073/pnas.2426179122
Cells. 2025 May 03. pii: 672. [Epub ahead of print]14(9):

Iron Metabolism and Muscle Aging: Where Ferritinophagy Meets Mitochondrial Quality Control.

Rosa Di Lorenzo, Emanuele Marzetti, Helio José Coelho-Junior, Riccardo Calvani, Vito Pesce, Francesco Landi, Christiaan Leeuwenburgh, Anna Picca.

  In older adults with reduced physical performance, an increase in the labile iron pool within skeletal muscle is observed. This accumulation is associated with an altered expression of mitochondrial quality control (MQC) markers and increased mitochondrial DNA damage, supporting the hypothesis that impaired MQC contributes to muscle dysfunction during aging. The autophagy-lysosome system plays a critical role in MQC by tagging and engulfing proteins and organelles for degradation in lysosomes. The endolysosomal system is also instrumental in transferrin recycling, which, in turn, regulates cellular iron uptake. In the neuromuscular system, the autophagy-lysosome system supports the structural integrity of neuromuscular junctions, and its dysfunction contributes to muscle atrophy. While MQC was thought to protect against iron-induced cell death, the discovery of ferroptosis, a form of iron-dependent cell death, has highlighted a complex interplay between MQC and iron-inflicted damage. Ferritinophagy, the autophagic degradation of ferritin, if overactivated, can induce ferroptosis. Alternatively, aging may impair ferritinophagy, leading to ferritin accumulation and the release of toxic labile iron under stress, exacerbating oxidative damage and cellular senescence. Physical activity supports muscle health also by preserving mitochondrial quantity and quality and enhancing bioenergetics. However, therapeutic strategies for preventing or reversing physical function decline in aging are still lacking due to the insufficient understanding of the underlying mechanisms. Unveiling how disruptions in iron homeostasis impact muscle quality in older adults may allow for the development of therapeutic strategies targeting iron handling to alleviate age-associated muscle decline.

Keywords:  autophagy; cytokine; endolysosomal system; hepcidin; inflammation; labile iron; mitophagy; physical performance; sarcopenia; transferrin

DOI:  https://doi.org/10.3390/cells14090672
Skelet Muscle. 2025 May 14. 15(1): 13

GsMTx4-blocked PIEZO1 channel promotes myogenic differentiation and alleviates myofiber damage in Duchenne muscular dystrophy.

Wengang Wang, Mingyang Huang, Xiusheng Huang, Ke Ma, Ming Luo, Ningning Yang.

   BACKGROUND: Duchenne muscular dystrophy (DMD) is a debilitating disease characterized by progressive muscle-wasting and a lack of effective therapy. Although the application of GsMTx4 has been shown to reduce muscle mass loss in dystrophic mice, the mechanism of action remains unclear.
METHODS: We employed single-nucleus RNA sequencing data to scrutinize the expression of mechanosensitive channels in skeletal muscle. The upregulation of PIEZO1 and its precise localization were corroborated in DMD patients, mdx mice, and activated satellite cells. To delve into the role of the GsMTx4-blocked PIEZO1 channel in the myogenic program, we conducted comprehensive in vitro and in vivo studies encompassing the proliferation of satellite cells, differentiation of myoblasts, and calcium influx into myofibers. Utilizing both a PIEZO1 channel inhibitor, GsMTx4, and a PIEZO1 channel agonist, Yoda1, we explored the PIEZO1 channel's impact on satellite cell proliferation and myogenic differentiation. Additionally, we explored the protective effect of the PIEZO1 channel on myofiber calcium influx using mdx mouse models and isolated single myofibers.
RESULTS: PIEZO1 was upregulated in the muscle of DMD patients and was predominantly expressed in satellite cells and upregulated during satellite cell proliferation. Treatment with GsMTx4 increased the cross-sectional areas of myofibers and reduced the proportion of centrally nucleated fibers in mdx mice. GsMTx4 inhibited satellite cell proliferation while promoting myogenic differentiation. During myogenic differentiation, the YAP nuclear-cytoplasmic ratio increased in cells treated with GsMTx4 and showed a significant correlation with the nuclear localization of MyoG. In myofibers, GsMTx4 significantly reduced the level of p-CaMKII/CaMKII in muscle and calcium load.
CONCLUSIONS: PIEZO1 upregulation in DMD could potentially stem from an elevated proportion of proliferating satellite cells triggered by sarcolemma damage and muscle necrosis. The inhibition of the PIEZO1 channel by GsMTx4 plays a beneficial role in fostering myogenic differentiation and mitigating myofiber damage. The PIEZO1 channel emerges as a promising therapeutic target for addressing DMD.

Keywords:  Duchenne muscular dystrophy; GsMTx4; Myogenic differentiation; PIEZO1; Satellite cells

DOI:  https://doi.org/10.1186/s13395-025-00383-5
FASEB J. 2025 May 31. 39(10): e70631

Fatigue Resistance and Mitochondrial Adaptations to Isometric Interval Training in Dystrophin-Deficient Muscle: Role of Contractile Load.

Nao Yamauchi, Yuki Ashida, Azuma Naito, Nao Tokuda, Ayaka Niibori, Norio Motohashi, Yoshitsugu Aoki, Takashi Yamada.

  In normal mouse skeletal muscles, interval training (IT)-mimicking neuromuscular electrical stimulation enhances muscle fatigue resistance and mitochondrial content, with greater gains observed at high (100 Hz stimulation, IT100) compared to low (20 Hz stimulation, IT20) contractile load. In this study, we compared the effects of repeated IT100 and IT20 on fatigue resistance and mitochondrial adaptations in young male mdx52 mice (4- to 6-week-old), an animal model for Duchenne muscular dystrophy. Plantar flexor muscles were stimulated in vivo using supramaximal electrical stimulation to induce isometric contractions every other day for 4 weeks (a total of 15 sessions). In non-trained muscles of mdx52 mice, decreased fatigue resistance was associated with reduced citrate synthase activity, lower peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC-1α) protein expression, and diminished levels of mitochondrial respiratory chain complex II, and an increased percentage of Evans Blue dye-positive areas. IT100, but not IT20, markedly improved fatigue resistance and restored all these alterations in mdx52 mice. Furthermore, an acute session of IT100, but not IT20, led to increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and elevated mRNA levels of PGC-1α, which were blocked by the p38 MAPK inhibitor SB203580. These findings suggest that contractile load is a key determinant of isometric IT-induced improvements in fatigue resistance, even in dystrophin-deficient muscles, potentially through a p38 MAPK/PGC-1α-mediated increase in mitochondrial content.

Keywords:  contractile load; fatigue resistance; isometric interval training; mitochondria; muscular dystrophy

DOI:  https://doi.org/10.1096/fj.202500618RR
Hum Mol Genet. 2025 May 14. pii: ddaf074. [Epub ahead of print]

Neuromuscular junction transcriptome analysis of spinal and bulbar muscular atrophy mice implicates sarcomere gene expression and calcium flux dysregulation in disease pathogenesis.

Anastasia Gromova, Byeonggu Cha, Nhat Nguyen, Diya Garg, Connor Coscolluela, Laura M Strickland, David Luong, Fabiana Longo, Bryce L Sopher, Mai K ElMallah, Albert R La Spada.

  X-linked Spinal and Bulbar Muscular Atrophy (SBMA) is a rare, late-onset neuromuscular disease caused by a CAG repeat expansion mutation in the androgen receptor (AR) gene. SBMA is characterized by progressive muscle atrophy of both neurogenic and myopathic etiologies. Previous work has established that mutant AR expression in skeletal muscle could be a significant contributor to neuromuscular decline, yet the mechanisms involved remain ill-defined. As AR is a nuclear hormone receptor transcription factor, we sought to define early changes in gene expression in skeletal muscle of pre-symptomatic SBMA mice, with a focus on transcriptional changes at the neuromuscular junction (NMJ). We describe loss of key NMJ-specific genes in synaptic muscle regions of pre-symptomatic SBMA mice, while extrasynaptic muscle features a coordinated loss of sarcomere genes that coincides with ectopic re-expression of certain NMJ genes. Furthermore, SBMA muscle prominently features dysregulated calcium flux, likely stemming from a compensatory response to early atrophy that greatly exacerbates over time. The SERCA activator CDN1163 conferred a mild rescue in function and muscle size in SBMA mice, while genetic deletion of the gene encoding Myf6/MRF4, a negative regulator of sarcomere gene expression and predicted AR interactor, did not ameliorate muscle atrophy. These studies suggest that modulation of calcium flux could be a promising pharmacological target in SBMA.

Keywords:  androgen receptor; motor neuron disease; neuromuscular junction; spinal and bulbar muscular atrophy; transcriptome

DOI:  https://doi.org/10.1093/hmg/ddaf074
Front Physiol. 2025 ;16 1533394

Analysis of the mechanism of skeletal muscle atrophy from the pathway of decreased protein synthesis.

Peng Chen, Fangfang Jia, Meng Wang, Shengbo Yang.

  Skeletal muscle atrophy is associated with denervation, cancer, diabetes, aging, immobilization, and inflammation, which can significantly impair mobility. It is primarily attributable to increased protein catabolism alongside reduced protein synthesis, although the precise mechanisms underlying this process are not yet fully known. Unlike in the pathway driving increased catabolism, fewer studies have explored the mechanism underpinning muscle atrophy under reduced protein synthesis. Therefore, this study aimed to focus on summarizing relevant studies on the reduction of protein synthesis leading to skeletal muscle atrophy, as driven by alterations in pathways such as the insulin-like growth factor-1-phosphatidylinositol 3-kinase-protein kinase B-rapamycin signaling pathway, glycogen synthase kinase-3, glucocorticoids, 5'-adenosine monophosphate-activated protein kinase, branched-chain amino acid sensors, myostatin, long-term proinflammatory factors, oxidative stress and mitochondrial dysfunction, calciumion concentration, activating transcription factor 4, and glycyl-tRNA synthetase alterations. Consolidating these data will provide a foundation and theoretical basis for further investigation into the mechanisms of muscle atrophy from the perspective of reduced protein synthesis pathways.

Keywords:  mTOR; mechanism; pathway; protein synthesis; skeletal muscle atrophy

DOI:  https://doi.org/10.3389/fphys.2025.1533394
Arch Gerontol Geriatr. 2025 May 05. pii: S0167-4943(25)00148-7. [Epub ahead of print] 105891

Harmonizing WHO-ICOPE with muscle health to promote healthy longevity.

Liang-Kung Chen.



Keywords:  Frailty; Healthy aging; Intrinsic capacity; Muscle health; Sarcopenia

DOI:  https://doi.org/10.1016/j.archger.2025.105891
Front Neurol. 2025 ;16 1556120

Muscle-specific kinase levels in blood are an early diagnostic biomarker for SOD1-93A mouse model of ALS.

Shuuichi Mori, Heying Zhou, Takuya Omura, Hiroki Tsumoto, Yuri Miura, Kazuhiro Shigemoto.

  Neuromuscular junction (NMJ) denervation is an early event preceding motor neuron loss in amyotrophic lateral sclerosis (ALS). Progressive loss of the NMJ leads to irreversible muscle weakness and atrophy. Muscle-specific kinase (MuSK), locally expressed at the postsynaptic membrane of the NMJ, is activated by agrin released from motor nerve terminals and is essential for NMJ maintenance and regeneration. Here, we found that the progression of NMJ denervation prior to the onset of muscle weakness in SOD1-93A mouse model of ALS correlated with increased serum MuSK immunoreactivity and elevated MuSK expression throughout the skeletal muscle. Our results suggest that neuromuscular failure associated with the onset of muscle weakness increases MuSK expression throughout the muscle, which is subsequently cleaved by proteolytic enzymes to increase MuSK immunoreactivity in the blood. These results demonstrate that the level of serum MuSK immunoreactivity may indicate the early phase of NMJ denervation and serve as a biomarker for assessing the progression of other types of ALS and therapeutic benefits in preclinical studies.

Keywords:  MuSK; NMJ; SOD1 mouse G93A; biomarker; diagnosis; mouse model

DOI:  https://doi.org/10.3389/fneur.2025.1556120
Cell Rep Methods. 2025 May 02. pii: S2667-2375(25)00084-0. [Epub ahead of print] 101048

Site-specific quantification of the in vivo UFMylome reveals myosin modification in ALS.

Ronnie Blazev, Barry M Zee, Hayley Peckham, Yaan-Kit Ng, Christopher T A Lewis, Chengxin Zhang, James W McNamara, Craig A Goodman, Paul Gregorevic, Julien Ochala, Frederik J Steyn, Shyuan T Ngo, Matthew P Stokes, Benjamin L Parker.

  UFMylation is a ubiquitin-like protein modification of Ubiquitin Fold Modifier 1 (UFM1) applied to substrate proteins and regulates several cellular processes such as protein quality control. Here, we describe the development of an antibody-based enrichment approach to immunoprecipitate remnant UFMylated peptides and identification by mass spectrometry. We used this approach to identify >200 UFMylation sites from various mouse tissues, revealing extensive modification in skeletal muscle. In vivo knockdown of the E2 ligase, UFC1, followed by enrichment and analysis of remnant UFMylated peptides quantified concomitant down-regulation and validation of a subset of modification sites, particularly myosin UFMylation. Furthermore, we show that UFMylation is increased in skeletal muscle biopsies from people living with amyotrophic lateral sclerosis (plwALS). Quantification of UFMylation sites in these biopsies with multiplexed isotopic labeling reveal prominent increases in myosin UFMylation. Our data suggest that in vivo UFMylation is more complex than previously thought.

Keywords:  CP: cell biology; UFM1; UFMylation; Ubiquitin Fold Modifier 1; ubiquitin-like modification

DOI:  https://doi.org/10.1016/j.crmeth.2025.101048
J Physiol. 2025 May 11.

ErbB2 as a therapeutic target for post-trauma muscle recovery.

Nasrin Dabirian, Chunyu Wang.



Keywords:  ErbB2 inhibition; innervation; muscle; muscle graft; neuromuscular junction imaging; volumetric muscle loss

DOI:  https://doi.org/10.1113/JP288895
Adv Healthc Mater. 2025 May 13. e2405111

Modeling Idiopathic Inflammatory Myopathy in the Bioinspired Muscle Tissue on Chip.

Xu Zhang, Mengqian Zhao, Pengwei Deng, Haitao Liu, Hongjing Li, Xiaoqing Zhang, Daqing Wang, Jianhua Qin.

  Idiopathic inflammatory myopathy (IIM) is an autoimmune disease that characterized by non-purulent inflammation of the skeletal muscle. However, due to the limitation of study model that can recapitulate the complex pathological process of IIM, the pathogenesis of IIM is still not fully clear. This manuscript develops a vascularized muscle tissue model on a chip that allows to model the immunity mediated pathological changes in IIM. This vascularized muscle model is constructed by layer-by-layer assembly, which could coculture of endothelial cells, myoblasts, and monocytes in a perfusable 3D system. The vascularized muscle model exhibits good biofunctions, including muscle cells alignment and fusion, myofibers generation, force production and expression of muscular biomarkers (myosin heavy chains 1, myosin heavy chains 7, actinin alpha 2, myogenin, and Desmin). Exposure to perfusion of activated monocytes, this work observes the functional changes of muscle tissue, which referred to myofibers atrophy, inflammatory response, and downregulated expression of muscle mature marker, consistent with clinical features of IIM. This work provides a unique platform for modelling IIM and paves a promising avenue for myopathies study and drug testing.

Keywords:  idiopathic inflammatory myopathy modelling; monocytes activation; skeletal muscle on chip; vascularization

DOI:  https://doi.org/10.1002/adhm.202405111
J Physiol. 2025 May 11.

The contribution of age and sex hormones to female neuromuscular function across the adult lifespan.

Steven J O'Bryan, Annabel Critchlow, Cas J Fuchs, Danielle Hiam, Séverine Lamon.

  Neuromuscular ageing is characterized by neural and/or skeletal muscle degeneration that decreases maximal force and power. Female neuromuscular ageing occurs earlier in life compared to males, potentially due to sex hormone changes during the menopausal transition. We quantified neuromuscular function in 88 females represented equally over each decade from 18 to 80 years of age and investigated the role of decreased ovarian hormone concentrations following menopause. Neuromuscular assessment included quadriceps maximal voluntary and evoked isometric torque and surface electromyography measurements, plus one-repetition maximum leg press. Voluntary and evoked torques and one-repetition maximum decreased non-linearly with age, with accelerated reductions starting during the fourth decade. An absence of changes in volitional recruitment of existing quadriceps motor units and Ia afferent facilitation of spinal motoneurons suggests that functional decline was largely mediated by impairment in intrinsic peripheral muscle function and/or neuromuscular transmission. Maximal muscle compound action potential amplitude decreased with increasing age for rectus femoris muscle only, indicating increased vulnerability to neuromuscular degeneration compared to vastus lateralis and medialis. In postmenopausal females, some variance was explained by inter-individual differences in quadriceps tissue composition and lifestyle factors, but changes in total or free concentrations of oestradiol, progesterone and/or testosterone were included in all correlations with age-related decreases in isometric voluntary and evoked torques. We demonstrate an accelerated onset of neuromuscular degeneration of peripheral muscular origin around menopause onset associated with changes in sex hormone concentrations. Interventions aimed at mitigating declines in ovarian hormones and their subsequent effects on neuromuscular function after menopause should be further explored. KEY POINTS: Neuromuscular deterioration with age is associated with poor physical function and quality of life in older adults, but female-specific trajectories and mechanisms remain unclear. This study is the first to map neuromuscular function across each decade of the adult lifespan in 88 females from 18 to 80 years old and to examine the potential role of hormonal changes after menopause. We show an accelerated reduction in neuromuscular function, primarily of peripheral muscular origin, that occurs during the fourth decade and coincides with menopause onset. In postmenopausal females, age-related reductions in neuromuscular function can in part be explained by quadriceps lean and intramuscular fat composition, physical activity and protein intake, and sex hormone concentrations. These findings help us better understand the factors that contribute to the loss of neuromuscular function with age in females, enabling the identification of potential therapeutic interventions to prolong female health span.

Keywords:  H‐reflex; M‐wave; bone density; muscle mass; older adults; premenopause; strength; voluntary activation

DOI:  https://doi.org/10.1113/JP287496
Narra J. 2025 Apr;5(1): e1764

Identification of differentially expressed genes in resting human skeletal muscle of sedentary versus strength and endurance- trained individuals using bioinformatics analysis and in vitro validation.

Rias G Kinanti, Anditri Weningtyas, Kiky M Ariesaka, Sendhi T Puspitasari, Ni Lka Arsani, Hung E Liao.

  Understanding the molecular mechanisms underlying skeletal muscle adaptation to different training regimens is essential for advancing muscle health and performance interventions. The aim of this study was to investigate molecular and genetic adaptations in the resting skeletal muscle of sedentary individuals compared to strength- and endurance-trained athletes using bioinformatics and in vitro validation. Differentially expressed genes (DEG) analysis of the GSE9405 dataset was conducted. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed, followed by protein-protein interaction (PPI) network analysis and receiver operating characteristic (ROC) analysis. To validate the bioinformatics findings, the expression of two identified genes was assessed using real-time polymerase chain reaction (PCR) in professional athletes and age-matched non-athletes. Analysis of RNA expression profiles from the GSE9405 dataset identified 426 DEGs, with 165 upregulated and 261 downregulated in trained individuals. Enrichment analysis highlighted pathways related to metabolic efficiency, mitochondrial function, and muscle remodeling, all crucial for athletic performance. PRKACA and CALM3 were identified as key upregulated genes in trained individuals with central roles in these pathways. The area under the curve (AUC) values for CALM3 and PRKACA were 0.8558 and 0.8846, respectively, for differentiating the two groups. Validation in human samples confirmed that CALM3 expression was significantly higher in athletes (p = 0.00i), suggesting its critical role in muscle adaptation. However, PRKACA expression differences between the groups were not statistically significant (p = 0.32i). These findings provide insights into gene-level responses to long-term training, offering a basis for targeted interventions to enhance muscle health and athletic performance.

Keywords:  CALM3; PRKACA; Skeletal muscle; gene expression regulation; physical endurance

DOI:  https://doi.org/10.52225/narra.v5i1.1764
Research (Wash D C). 2025 ;8 0699

Microdroplet-Engineered Skeletal Muscle Organoids from Primary Tissue Recapitulate Parental Physiology with High Reproducibility.

Jiawei Li, Yiming Yang, Ziqi Yi, Yu Zhu, Haowei Yang, Baiming Chen, Peter E Lobie, Shaohua Ma.

Achieving high maturity and functionality in in vitro skeletal muscle models is essential for advancing our understanding of muscle biology, disease mechanisms, and drug discovery. However, current models struggle to fully recapitulate key features such as sarcomere structure, muscle fiber composition, and contractile function while also ensuring consistency and rapid production. Adult stem cells residing in muscle tissue are known for their powerful regenerative potential, yet tissue-derived skeletal muscle organoids have not been established. In this study, we introduce droplet-engineered skeletal muscle organoids derived from primary tissue using cascade-tubing microfluidics. These droplet-engineered organoids (DEOs) exhibit high maturity, including well-developed striated sarcomeres, spontaneous and stimulated contractions, and recapitulation of parental muscle fiber types. Notably, DEOs are produced in just 8 d without the need for primary cell culture-substantially accelerating the 50- to 60-d process required by classical organoid models. Additionally, the cascade-tubing microfluidics platform enables high-throughput production of hundreds of uniform DEO replicates from a small tissue sample, providing a scalable and reproducible solution for skeletal muscle research and drug screening.

DOI: https://doi.org/10.34133/research.0699
Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2502652122

A combined experimental and computational analysis of mantATP turnover in skinned muscle fibers.

Mauro Montesel, Cosimo De Napoli, Luisa Schmidt, Elena Germinario, Ulises H Guzman, Jesper V Olsen, Lorenzo Marcucci, Leonardo Nogara.

  Myosin is the primary motor protein in skeletal muscle, responsible for adenosine triphosphate (ATP) hydrolysis that drives muscle contraction. In addition to force production, resting myosin consumes ATP in futile cycles at two rates, the slower one being associated with the Super Relaxed State (SRX), in contrast to the less inhibited Disordered Relaxed State (DRX). The SRX is typically measured using the mantATP chasing technique, where the decay of a fluorescent ATP analogue is fitted using a multiexponential function. Recently, significant concerns have been raised regarding the use of this technique, particularly when applied to soluble myosin preparations. While skinned fibers offer the advantage of preserving the native thick filament structure and myosin cooperativity, limited diffusion and nonspecific mantATP binding pose challenges. In this study, we combine experimental data and in-silico modeling to dissect the contributions of different components in the mantATP chasing signal. We analyze control skinned fibers and fibers subjected to myosin extraction. Our analysis shows that the nonspecific component partially overlaps with the DRX timescale. In contrast, the slow component linked to myosin SRX nucleotide release is characterized by a time constant that significantly differs from those of the nonspecific signal and DRX, enabling its reliable estimation using this technique. Our findings indicate that evaluating nonspecific mantATP components is necessary to obtain a reliable estimation of both SRX and DRX. We validated our analysis by comparing populations and time constants obtained from chasing with mantATP to mantATPase rates in control conditions and upon piperine-induced SRX destabilization.

Keywords:  ATPase; mantATP chasing; modeling; myosin; skeletal muscle

DOI:  https://doi.org/10.1073/pnas.2502652122
Int J Mol Sci. 2025 Apr 25. pii: 4092. [Epub ahead of print]26(9):

Luteolin Induces Nrf2 Activity in C2C12 Cells: Implications for Muscle Health.

Nicole Böttcher, Frank Suhr, Thomas Pufe, Christoph Jan Wruck, Athanassios Fragoulis.

  Chronic oxidative distress results in cellular damage, necessitating adaptive mechanisms for redox balance. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is pivotal in the regulation of key antioxidant and cytoprotective genes. Under normal conditions, Nrf2 undergoes rapid degradation through polyubiquitination. However, it can be activated during oxidative eustress and distress via modifications of its inhibitor Kelch-like ECH-associated protein 1 (KEAP1). Activation of the Nrf2-Keap1 signaling pathway may decelerate aging-related muscle degeneration, such as sarcopenia and cachexia. In this study, we investigated the efficacy of two muscle-active endogenous factors, creatine and L-β-aminoisobutyric acid (L-BAIBA), as well as two natural phytochemicals, luteolin and silibinin, to induce Nrf2 in the murine myoblast cell line C2C12. Our results revealed that only luteolin significantly enhances Nrf2 activity in both proliferating and differentiated C2C12 cells, leading to increased expression of Nrf2 target genes in proliferating C2C12 cells. In contrast, the other three compounds had either no or only minor effects on Nrf2 activity or target gene expression. Our results underscore the distinct responses of C2C12 cells to different Nrf2 activators, emphasizing the significance of cellular context in their biological effects and highlight luteolin as a potential future treatment option to counteract muscle wasting associated with sarcopenia and cachexia.

Keywords:  C2C12 myoblasts; Nrf2; Nrf2 activators; SkM; luteolin; skeletal muscle

DOI:  https://doi.org/10.3390/ijms26094092
Histol Histopathol. 2025 Apr 30. 18929

Recent insights into limb-girdle muscular dystrophy: Impacts, therapy, and challenges.

Chen-Chen Sun, Jiang-Ling Xiao, Zhe Zhao, Heng-Yuan Liu, Chang-Fa Tang.

Limb-girdle muscular dystrophy (LGMD) is a genetically heterogeneous group of muscle disorders characterized by progressive muscle atrophy and loss of motor function. Over 30 subtypes have been identified and classified into two main inheritance patterns: autosomal dominant and autosomal recessive. Besides primarily affecting skeletal muscle, certain subtypes also impact the cardiac and respiratory muscles, significantly influencing disease progression and patient survival. Substantial progress has been made in understanding the pathogenic genes and molecular mechanisms of LGMD; however, developing disease-modifying therapies remains challenging due to genetic heterogeneity, limitations in gene delivery technologies, and secondary pathological complications. Current treatments are primarily supportive, focusing on symptom management and improving quality of life rather than addressing the underlying cause. This paper summarizes recent advances in LGMD pathogenesis and emerging therapeutic strategies, highlighting progress and remaining challenges in the field.

DOI: https://doi.org/10.14670/HH-18-929
Biochemistry (Mosc). 2025 Mar;90(3): 349-363

Development of Immunochemical Systems for Detection of Human Skeletal Troponin I Isoforms.

Agnessa P Bogomolova, Ivan A Katrukha, Alexey M Emelin, Artur I Zabolotsky, Anastasia V Bereznikova, Olga S Lebedeva, Roman V Deev, Alexey G Katrukha.

  Troponin I (TnI), together with troponin T (TnT) and troponin C (TnC), forms the troponin complex, a thin filament protein of the striated muscle that plays a key role in regulation of muscle contraction. In humans, TnI is represented by three isoforms: cardiac, which is synthesized only in myocardium, and fast and slow skeletal, which are synthesized in fast- and slow-twitch muscle fibers, respectively. Skeletal TnI isoforms could be used as biomarkers of skeletal muscle damage of various etiologies, including mechanical trauma, myopathies, muscle atrophy (sarcopenia), and rhabdomyolysis. Unlike classical markers of muscle damage, such as creatine kinase or myoglobin, which are also present in other tissues, skeletal TnIs are specific for skeletal muscle. In this study, we developed a panel of monoclonal antibodies for immunochemical detection of skeletal TnI isoforms using Western blotting (sensitivity: 0.01-1 ng per lane), immunohistochemical assays, and fluorescence immunoassays. Some of the designed fluorescence immunoassays enable quantification of fast skeletal (limit of detection [LOD] = 0.07 ng/mL) and slow skeletal (LOD = 0.1 ng/mL) TnI isoforms or both isoforms (LOD = 0.1 ng/ml). Others allow differential detection of binary (with TnC) or ternary (with TnT and TnC) complexes, revealing composition of troponin forms in the human blood.

Keywords:  biomarker; fast skeletal troponin I; immunoassays; immunochemical detection; monoclonal antibodies; myopathy; skeletal muscle damage; slow skeletal troponin I; troponin

DOI:  https://doi.org/10.1134/S0006297924601928
Nat Metab. 2025 May 15.

Mechanically sensitive MAPK signalling mediates resistance exercise-induced muscle growth.

Sue C Bodine, Craig A Goodman.

DOI: https://doi.org/10.1038/s42255-025-01303-z
J Physiol. 2025 May;603(9): 2675-2698

Adverse effects of high-fat diet consumption on contractile mechanics of isolated mouse skeletal muscle are reduced when supplemented with resveratrol.

Sharn P Shelley, Rob S James, Steven J Eustace, Mark C Turner, Ryan Brett, Emma L J Eyre, Jason Tallis.

  Increasing evidence indicates resveratrol (RES) supplementation evokes anti-obesogenic responses that could mitigate obesity-induced reductions in skeletal muscle (SkM) contractility. Contractile function is a key facet of SkM health that underpins whole body health. For the first time, the present study examines the effects of a high-fat diet and RES supplementation on isolated soleus (SOL) and extensor digitorum longus (EDL) contractile function. Female CD-1 mice, ∼6 weeks old (n = 38), consumed a standard laboratory diet (SLD) or a high-fat diet (HFD), with or without RES (4 g kg-1 diet) for 12 weeks. SOL and EDL (n = 8-10 per muscle, per group) were isolated and then absolute and normalised (to muscle size and body mass) isometric force and work loop power output (PO) were measured, and fatigue resistance was determined. Furthermore, sirtuin-1 expression was determined to provide mechanistic insight into any potential contractile changes. For SOL absolute force was higher in HFDRES compared to HFD (P = 0.033), and PO normalised to body mass and cumulative work during fatigue were reduced in HFD groups (P < 0.014). EDL absolute and normalised PO and cumulative work during fatigue were lower in HFD compared to other groups (P < 0.019). RES negated most adverse effects of HFD consumption on EDL contractility, with HFDRES producing PO and cumulative work comparable to the SLD groups. Sirtuin-1 expression was not influenced by diet in either muscle (P > 0.165). This study uniquely demonstrates that RES attenuates HFD-induced reductions in contractile performance of EDL, but this response is not explained by altered sirtuin-1 expression. These results suggest RES may be an appropriate strategy to alleviate obesity-induced declines in SkM function. KEY POINTS: Skeletal muscle health, a precursor for disease prevention, whole body health and quality of life, is substantially reduced because of obesity. Growing evidence suggests that the anti-obesogenic effects of nutritional supplement resveratrol may mitigate against obesity-induced muscle pathology. However, the effect of resveratrol on skeletal muscle contractile performance, a primary marker of skeletal muscle health, is yet to be examined. Our findings indicate that resveratrol reduces the adverse effects of high-fat diet consumption on the contractile performance of isolated fast twitch muscle and reduces the accumulation of central adipose. Resveratrol had little effect on skeletal muscle performance of standard diet mice, highlighting its specific efficacy in addressing high-fat diet-induced muscle pathology.

Keywords:  fatigue; force; muscle function; nutraceuticals; obesity; power output; work loop

DOI:  https://doi.org/10.1113/JP287056
Aging (Albany NY). 2025 May 08. 17

Cisd1 synergizes with Cisd2 to modulate protein processing by maintaining mitochondrial and ER homeostasis.

Yi-Fan Chen, Yuan-Chi Teng, Jian-Hsin Yang, Cheng-Heng Kao, Ting-Fen Tsai.

  Connection and crosstalk among the organelles critically contribute to cellular functions. Destruction of any kind of organelle is likely to induce a series of intracellular disorders and finally lead to cell death. Because of its subcellular locations, CDGSH iron-sulfur domain-containing protein 1 (Cisd1) and Cisd2 have functions that are related to maintaining mitochondria and ER homeostasis. As previous reports have shown, Cisd2 knockout mice have a decreased body weight and poor survival rate, and the primary defects were conducted in skeletal muscle. Our previous findings indicated that Cisd1 deletion causes a range of skeletal muscle defects in mice with Cisd2 deficiency, including mitochondrial degeneration, endoplasmic reticulum (ER) stress, and alteration of protein process, as well as programmed cell death. In Cisd1 and Cisd2 deficient condition, the whole of the protein biosynthesis was damaged, including translation, modification, transport, and degradation. Changes in the immune response, redox regulation, and metabolism were also present in Cisd1 and Cisd2 double knockout mice. Overall, we have demonstrated that Cisd1 and Cisd2 knockout have a synergistic effect on skeletal muscles, and that Cisd2 plays a more critical role than Cisd1. These synergistic effects impact signaling regulation and interrupt the crosstalk and homeostasis of organelles. This creates severe disorders in various tissues and organs.

Keywords:  Cisd1; Cisd2; ER stress; knockout mice; mitochondria; protein process; skeletal muscle

DOI:  https://doi.org/10.18632/aging.206249
J Cell Mol Med. 2025 May;29(9): e70588

Enhancement of Energy Metabolism in Skeletal Myocytes Protects Against Age-Related Sarcopenia.

Andrey Y Vinokurov, Pavel A Bazhenov, Marina Y Pogonyalova, Evgenia S Seryogina, Ekaterina A Vetrova, Larisa Andreeva, Andrey Y Abramov, Plamena R Angelova.

  Skeletal muscles constantly consume energy, and this consumption level increases correspondingly to the levels of physical activity. Mitochondrial energy metabolism requires constant supplementation with oxygen and substrates for ATP production. Limitation of the mitochondrial substrate supply leads to energy deprivation, which may be followed by sarcopenia and weight loss. Activation of mitochondrial energy metabolism can also stimulate the production of reactive oxygen species and oxidative stress. Here, we studied the effect of various mitochondrial substrates on the energy metabolism of primary skeletal myotubes and how it affects redox balance. We found that as individual components-glutamate, succinate, nicotinamide (NAM) as well as in combination-dicholine succinate (DISU) plus NAM, they increase mitochondrial membrane potential, alter NADH and FAD redox indices, which leads to an increased energy capacity of the skeletal myotubes. Changes in mitochondrial metabolism increased ROS production in mitochondria and cytosol but induced only a minor decrease in the level of the endogenous antioxidant reduced glutathione. Supplementation of young and aged rats with DISU + NAM through the drinking water for 7 days significantly increased myotube diameter in both age groups. Thus, provision of the myotubes with mitochondrial metabolism substrates activates energy metabolism and increases energy capacity but has no effect on oxidative stress. Moreover, it increases myotubes' diameters in young and aged rodent sarcopenia models in vivo.

Keywords:  energy metabolism; glutathione; mitochondria; myotubes; reactive oxygen species; sarcopenia

DOI:  https://doi.org/10.1111/jcmm.70588
bioRxiv. 2025 May 04. pii: 2025.04.29.649515. [Epub ahead of print]

Unacylated Ghrelin Counteracts Contractile and Mitochondrial Dysfunction in Cancer Cachexia.

Bumsoo Ahn, Jonathan Wanagat, Caroline Cleary, Hannah C Ainsworth, Eunyoung Kim, Hyunyoung Kim.

Background: Cancer cachexia is a complex metabolic syndrome that severely impacts patient mobility, treatment strategies, and quality of life. However, no treatments are available to mitigate the debilitating consequences of cancer cachexia. Unacylated ghrelin (UnAG), the main circulating form of ghrelin, enhances muscle growth and mitochondrial function in various diseases, but its effects in cancer cachexia remain to be tested.
Methods: Male C57Bl6/N mice were assigned to one of three treatment groups: non-tumor-bearing (NTB), tumor-bearing (TB), or tumor-bearing treated with unacylated ghrelin (TB+UnAG). Over four weeks, we monitored body weight, food intake, and tumor size. We assessed muscle mass, contractility, mitochondrial oxygen consumption rate (OCR), and reactive oxygen species (ROS) production. Proteomic analysis was performed to elucidate the downstream effects of UnAG. Cell culture assays were performed to measure the in vitro effects of cancer cell-secreted factors and UnAG on myoblasts.
Results: Gastrocnemius and quadriceps muscle masses were reduced by 20-30% in TB mice compared to NTB controls; however, UnAG treatment prevented approximately 50% of this loss. Beyond muscle mass, UnAG enhanced the isometric maximum specific force of the extensor digitorum longus by 70% in TB mice. This improvement in muscle quality was associated with preferential upregulation of myosin heavy chain expression in TB+UnAG mice. UnAG also increased mitochondrial OCR while reducing ROS production. Mitochondrial DNA (mtDNA) copy number, which was reduced in TB mice, was restored by UnAG, while the reduced mtDNA mutation frequency in TB mice was maintained with treatment, indicating improved mtDNA integrity. Consistent with enhanced mitochondrial function, treadmill running time was significantly increased in TB+UnAG mice. Proteomic analysis revealed that UnAG downregulated proteins associated with proteolysis, while normalizing antioxidant enzyme thioredoxin and proteins involved in calcium handling. Cancer cell-conditioned medium reduced myotube width in vitro, but UnAG treatment preserved myotube structure..
Conclusion: UnAG protects against cancer cachexia by targeting multiple risk factors, including myosin heavy chain expression, mitochondrial bioenergetics, and modulation of protein degradation pathways.

DOI: https://doi.org/10.1101/2025.04.29.649515
Nat Commun. 2025 May 13. 16(1): 4377

GDF8 and activin A blockade protects against GLP-1-induced muscle loss while enhancing fat loss in obese male mice and non-human primates.

Jason W Mastaitis, Daniel Gomez, José G Raya, Diana Li, Soo Min, Michael Stec, Sandra Kleiner, Toya McWilliams, Judith Y Altarejos, Andrew J Murphy, George D Yancopoulos, Mark W Sleeman.

Glucagon-like peptide-1 receptor agonists act via appetite suppression and caloric restriction. These treatments can result in significant muscle loss, likely due to evolutionary mechanisms protecting against food scarcity as muscle is a major energy utilizer. One mechanism that reduces muscle mass involves activation of type II activin receptors, ActRIIA/B, which yield profound muscle growth in humans when blocked. We previously demonstrated GDF8, also known as myostatin, and activin A are the two major ActRIIA/B ligands mediating muscle minimization. Here, we report that dual blockade can also prevent muscle loss associated with glucagon-like peptide-1 receptor agonists - and even increase muscle mass - in both obese mice and non-human primates; moreover, this muscle preservation enhances fat loss and is metabolically beneficial. These data raise the possibility that supplementing glucagon-like peptide-1 receptor agonist treatment with GDF8 and activin A blockade could greatly improve the quality of weight loss during the treatment of obesity in humans.

DOI: https://doi.org/10.1038/s41467-025-59485-9
Int J Mol Sci. 2025 May 07. pii: 4428. [Epub ahead of print]26(9):

Towards Precision in Sarcopenia Assessment: The Challenges of Multimodal Data Analysis in the Era of AI.

Valerio Caputo, Ivan Letteri, Silvano Junior Santini, Gaia Sinatti, Clara Balsano.

  Sarcopenia, a condition characterised by the progressive decline in skeletal muscle mass and function, presents significant challenges in geriatric healthcare. Despite advances in its management, complex etiopathogenesis and the heterogeneity of diagnostic criteria underlie the limited precision of existing assessment methods. Therefore, efforts are needed to improve the knowledge and pave the way for more effective management and a more precise diagnosis. To this purpose, emerging technologies such as artificial intelligence (AI) can facilitate the identification of novel and accurate biomarkers by modelling complex data resulting from high-throughput technologies, fostering the setting up of a more precise approach. Based on such considerations, this review explores AI's transformative potential, illustrating studies that integrate AI, especially machine learning and deep learning, with heterogeneous data such as clinical, anthropometric and molecular data. Overall, the present review will highlight the relevance of large-scale, standardised studies to validate biomarker signatures using AI-driven approaches.

Keywords:  artificial intelligence; circulating biomarkers; circulating proteome; diagnosis; machine learning; metabolome; molecular markers; multimodal analysis; nc-RNAs; sarcopenia

DOI:  https://doi.org/10.3390/ijms26094428