bims-moremu 2025-01-19 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–01–19
29 papers selected by
Anna Vainshtein, Craft Science Inc.

Fibroblast growth factor-inducible 14 regulates satellite cell self-renewal and expansion during skeletal muscle repair.
Exercise Therapy Rescues Skeletal Muscle Dysfunction and Exercise Intolerance in Cardiometabolic HFpEF.
Protocol for quantifying muscle fiber size, number, and central nucleation of mouse skeletal muscle cross-sections using Myotally software.
Effects of leg immobilization and recovery resistance training on skeletal muscle-molecular markers in previously resistance trained versus untrained adults.
Effects of HMG CoA reductase (HMGCR) deficiency on skeletal muscle development.
The Unexplored Role of Connexin Hemichannels in Promoting Facioscapulohumeral Muscular Dystrophy Progression.
Muscle-derived myostatin is a major endocrine driver of follicle-stimulating hormone synthesis.
Combined exercise-induced modulation of Notch pathway and muscle quality in senescence-accelerated mice.
Pan-cancer secreted proteome and skeletal muscle regulation: insight from a proteogenomic data-driven knowledge base.
The Effects of Glucagon-Like Peptide-1 Receptor Agonists on Mitochondrial Function Within Skeletal Muscle: A Systematic Review.
Iron Chelation Prevents Age-Related Skeletal Muscle Sarcopenia in Klotho Gene Mutant Mice, a Genetic Model of Aging.
Dehydroandrographolide Succinate Attenuates Dexamethasone-Induced Skeletal Muscle Atrophy by Regulating Akt/GSK3β and MuRF-1 Pathways.
Protective effects of Lactobacillus plantarum strain against protein malnutrition-induced muscle atrophy and bone loss in juvenile mice.
Unraveling calcium dysregulation and autoimmunity in immune mediated rippling muscle disease.
Unravelling the transcriptomic symphony of muscle ageing: key pathways and hub genes altered by ageing and caloric restriction in rat muscle revealed by RNA sequencing.
Ablation of satellite cell-specific clock gene, Bmal1, alters force production, muscle damage, and repair following contractile-induced injury.
Local Inflammation Precedes Diaphragm Wasting and Fibrotic Remodelling in a Mouse Model of Pancreatic Cancer.
A Homozygous ATP2A2 Variant Alters Sarcoendoplasmic Reticulum Ca2+-ATPase 2 Function in Skeletal Muscle and Causes a Novel Vacuolar Myopathy.
Heat boost: therapeutic approach for skeletal muscle health and postprandial mechanisms in older adults.
Mechanisms of Skeletal Muscle Dysfunction in Cardiometabolic HFpEF and Its Reversal With Exercise Training.
Protocol for the three-dimensional analysis of rodent skeletal muscle.
Aptamer-conjugated gold nanoparticles enable oligonucleotide delivery into muscle stem cells to promote regeneration of dystrophic muscles.
Focus on the Forgotten Organelle: Regulation of Lysosomes in Skeletal Muscle.
Role of PI3 Kinases in Cell Signaling and Soleus Muscle Atrophy During Three Days of Unloading.
Titin fragment is a sensitive biomarker in Duchenne muscular dystrophy model mice carrying full-length human dystrophin gene on human artificial chromosome.
Effects of defined voluntary running distances coupled with high-fat diet consumption on the skeletal muscle transcriptome of male mice.
Aminoguanidine hemisulfate improves mitochondrial autophagy, oxidative stress, and muscle force in Duchenne muscular dystrophy via the AKT/FOXO1 pathway in mdx mice.
Impaired hydrogen sulfide biosynthesis underlies eccentric contraction-induced force loss in dystrophin-deficient skeletal muscle.
From molecular to physical function: The aging trajectory.

bioRxiv. 2025 Jan 02. pii: 2024.10.06.616900. [Epub ahead of print]

Fibroblast growth factor-inducible 14 regulates satellite cell self-renewal and expansion during skeletal muscle repair.

Meiricris Tomaz da Silva, Aniket S Joshi, Ashok Kumar.

  Skeletal muscle regeneration in adults is predominantly driven by satellite cells. Loss of satellite cell pool and function leads to skeletal muscle wasting in many conditions and disease states. Here, we demonstrate that the levels of fibroblast growth factor-inducible 14 (Fn14) are increased in satellite cells after muscle injury. Conditional ablation of Fn14 in Pax7-expressing satellite cells drastically reduces their expansion and skeletal muscle regeneration following injury. Fn14 is required for satellite cell self-renewal and proliferation as well as to prevent precocious differentiation. Targeted deletion of Fn14 inhibits Notch signaling but leads to the spurious activation of STAT3 signaling in regenerating skeletal muscle and in cultured muscle progenitor cells. Silencing of STAT3 improves proliferation and inhibits premature differentiation of Fn14-deficient satellite cells. Furthermore, conditional ablation of Fn14 in satellite cells exacerbates myopathy in the mdx mouse model of Duchenne muscular dystrophy (DMD) whereas its overexpression improves the engraftment of exogenous muscle progenitor cells into the dystrophic muscle of mdx mice. Altogether, our study highlights the crucial role of Fn14 in the regulation of satellite cell fate and function and suggests that Fn14 can be a potential molecular target to improve muscle regeneration in muscular disorders.

Keywords:  Muscle regeneration; Muscular dystrophy; Notch; Satellite cells; Stat3

DOI:  https://doi.org/10.1101/2024.10.06.616900
JACC Basic Transl Sci. 2024 Dec;9(12): 1409-1425

Exercise Therapy Rescues Skeletal Muscle Dysfunction and Exercise Intolerance in Cardiometabolic HFpEF.

Heather Quiriarte, Robert C Noland, James E Stampley, Gregory Davis, Zhen Li, Eunhan Cho, Youyoung Kim, Jake Doiron, Guillaume Spielmann, Sujoy Ghosh, Sanjiv J Shah, Brian A Irving, David J Lefer, Timothy D Allerton.

  Exercise intolerance, a hallmark of heart failure with preserved ejection fraction (HFpEF) exacerbated by obesity, involves unclear mechanisms related to skeletal muscle metabolism. In a "2-hit" model of HFpEF, we investigated the ability of exercise therapy (voluntary wheel running) to reverse skeletal muscle dysfunction and exercise intolerance. Using state-of-the-art metabolic cages and a multiomic approach, we demonstrate exercise can rescue dysfunctional skeletal muscle lipid and branched-chain amino acid oxidation and restore exercise capacity in mice with cardiometabolic HFpEF. These results underscore the importance of skeletal muscle metabolism to improve exercise intolerance in HFpEF.

Keywords:  branched-chained amino acids; exercise; heart failure with preserved ejection fraction; metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.jacbts.2024.07.009
STAR Protoc. 2025 Jan 10. pii: S2666-1667(24)00720-2. [Epub ahead of print]6(1): 103555

Protocol for quantifying muscle fiber size, number, and central nucleation of mouse skeletal muscle cross-sections using Myotally software.

Pieter Both, Soochi Kim, Jengmin Kang, Marina Arjona, Daniel I Benjamin, Christopher W Nutter, Armon Goshayeshi, Thomas A Rando.

  Here, we present a protocol for using Myotally, a user-friendly software for fast, automated quantification of muscle fiber size, number, and central nucleation from immunofluorescent stains of mouse skeletal muscle cross-sections. We describe steps for installing the software, preparing compatible images, finding the file path, and selecting key parameters like image quality and size limits. We also detail optional features, such as measuring mean fluorescence. By automating these traditionally labor-intensive processes, Myotally improves research efficiency and data consistency.

Keywords:  Cell Biology; Computer sciences; Microscopy

DOI:  https://doi.org/10.1016/j.xpro.2024.103555
J Appl Physiol (1985). 2025 Jan 16.

Effects of leg immobilization and recovery resistance training on skeletal muscle-molecular markers in previously resistance trained versus untrained adults.

J Max Michel, Joshua S Godwin, Daniel L Plotkin, Mason C McIntosh, Madison L Mattingly, Philip J Agostinelli, Breanna J Mueller, Derick A Anglin, Nicholas J Kontos, Alexander C Berry, Marina Meyer Vega, Autumn A Pipkin, Matt S Stock, Zachary A Graham, Harsimran S Baweja, C Brooks Mobley, Marcas M Bamman, Michael D Roberts.

  We sought to examine how resistance training (RT) status in young healthy individuals, either well resistance trained (T, n=10) or untrained (UT, n=11), affected molecular markers with leg immobilization followed by recovery RT. All participants underwent two weeks of left leg immobilization via a locking leg brace. Afterwards, all participants underwent eight weeks (3 d/week) of knee extensor focused progressive RT. Vastus lateralis (VL) ultrasound-derived thickness and muscle cross-sectional area were measured at baseline (PRE), immediately after disuse (MID), and after RT (POST) with VL muscle biopsies also being collected at these time points. Both groups presented lower ultrasound derived VL size metrics at MID versus PRE (p<0.001), and values increased in both groups from MID to POST (p<0.05); however, VL size increased from PRE to POST in UT only (p<0.001). Mean and type II myofiber cross-sectional area values were greater at PRE and POST versus MID (p<0.05), with T being greater than UT throughout (P<0.012). In both groups, satellite cell number was not affected by leg immobilization but increased in response to RT (p<0.014), with T being greater than UT throughout (p=0.004). Total RNA (ribosome content) decreased (p=0.010) from PRE to MID, while total RNA and certain endoplasmic reticulum stress proteins increased from MID to POST regardless of training status. Immobilization-induced muscle atrophy and recovery RT hypertrophy outcomes are similar between UT and T participants, and the lack of molecular signature differences between groups supports these findings. However, results are limited to younger adults undergoing non-complicated disuse.

Keywords:  atrophy; bracing; hypertrophy; immobilization

DOI:  https://doi.org/10.1152/japplphysiol.00837.2024
FEBS J. 2025 Jan 16.

Effects of HMG CoA reductase (HMGCR) deficiency on skeletal muscle development.

Mekala Gunasekaran, Hannah R Littel, Natalya M Wells, Johnnie Turner, Gloriana Campos, Sree Venigalla, Elicia A Estrella, Partha S Ghosh, Audrey L Daugherty, Seth A Stafki, Louis M Kunkel, A Reghan Foley, Sandra Donkervoort, Carsten G Bönnemann, Laura Toledo-Bravo de Laguna, Andres Nascimento, Daniel Natera-de Benito, Isabelle Draper, Christine C Bruels, Christina A Pacak, Peter B Kang.

  Pathogenic variants in HMGCR were recently linked to a limb-girdle muscular dystrophy (LGMD) phenotype. The protein product HMG CoA reductase (HMGCR) catalyzes a key component of the cholesterol synthesis pathway. The two other muscle diseases associated with HMGCR, statin-associated myopathy (SAM) and autoimmune anti-HMGCR myopathy, are not inherited in a Mendelian pattern. Statins inhibit HMGCR activity to generate their cholesterol-lowering effects and are known to cause multiple types of adverse effects on skeletal muscle, while the antibodies associated with anti-HMGCR myopathy specifically target this enzyme. The mechanism linking pathogenic variants in HMGCR with skeletal muscle dysfunction is unclear. We knocked down Hmgcr in mouse skeletal myoblasts, knocked down hmgcr in Drosophila, and expressed three pathogenic HMGCR variants (c.1327C>T, p.Arg443Trp; c.1522_1524delTCT, p.Ser508del; and c.1621G>A, p.Ala541Thr) in Hmgcr knockdown mouse myoblasts. Hmgcr deficiency was associated with decreased proliferation, increased apoptosis, and impaired myotube fusion. Transcriptome sequencing of Hmgcr knockdown versus control myoblasts revealed differential expression involving mitochondrial function, with corresponding differences in cellular oxygen consumption rates. Both ubiquitous and muscle-specific knockdown of hmgcr in Drosophila led to lethality. Overexpression of reference HMGCR cDNA rescued myotube fusion in knockdown cells, whereas overexpression of the pathogenic variants of HMGCR cDNA did not. These results suggest that the three HMGCR-related muscle diseases share disease mechanisms related to skeletal muscle development.

Keywords:  HMGCR; muscular dystrophy; myoblast; skeletal muscle; statin myopathy

DOI:  https://doi.org/10.1111/febs.17406
Int J Mol Sci. 2025 Jan 04. pii: 373. [Epub ahead of print]26(1):

The Unexplored Role of Connexin Hemichannels in Promoting Facioscapulohumeral Muscular Dystrophy Progression.

Macarena Díaz-Ubilla, Mauricio A Retamal.

  DUX4 is typically a repressed transcription factor, but its aberrant activation in Facioscapulohumeral Muscular Dystrophy (FSHD) leads to cell death by disrupting muscle homeostasis. This disruption affects crucial processes such as myogenesis, sarcolemma integrity, gene regulation, oxidative stress, immune response, and many other biological pathways. Notably, these disrupted processes have been associated, in other pathological contexts, with the presence of connexin (Cx) hemichannels-transmembrane structures that mediate communication between the intracellular and extracellular environments. Thus, hemichannels have been implicated in skeletal muscle atrophy, as observed in human biopsies and animal models of Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Dysferlinopathies, suggesting a potentially shared mechanism of muscle atrophy that has not yet been explored in FSHD. Despite various therapeutic strategies proposed to manage FSHD, no treatment or cure is currently available. This review summarizes the current understanding of the mechanisms underlying FSHD progression, with a focus on hormones, inflammation, reactive oxygen species (ROS), and mitochondrial function. Additionally, it explores the potential of targeting hemichannels as a therapeutic strategy to slow disease progression by preventing the spread of pathogenic factors between muscle cells.

Keywords:  connexin; hemichannels; muscular dystrophy; therapy

DOI:  https://doi.org/10.3390/ijms26010373
Science. 2025 Jan 17. 387(6731): 329-336

Muscle-derived myostatin is a major endocrine driver of follicle-stimulating hormone synthesis.

Luisina Ongaro, Xiang Zhou, Ying Wang, Hailey Schultz, Ziyue Zhou, Evan R S Buddle, Emilie Brûlé, Yeu-Farn Lin, Gauthier Schang, Adam Hagg, Roselyne Castonguay, Yewei Liu, Gloria H Su, Nabil G Seidah, Kevin C Ray, Seth J Karp, Ulrich Boehm, Frederique Ruf-Zamojski, Stuart C Sealfon, Kelly L Walton, Se-Jin Lee, Daniel J Bernard.

Myostatin is a paracrine myokine that regulates muscle mass in a variety of species, including humans. In this work, we report a functional role for myostatin as an endocrine hormone that directly promotes pituitary follicle-stimulating hormone (FSH) synthesis and thereby ovarian function in mice. Previously, this FSH-stimulating role was attributed to other members of the transforming growth factor-β family, the activins. Our results both challenge activin's eponymous role in FSH synthesis and establish an unexpected endocrine axis between skeletal muscle and the pituitary gland. Our data also suggest that efforts to antagonize myostatin to increase muscle mass may have unintended consequences on fertility.

DOI: https://doi.org/10.1126/science.adi4736
Pflugers Arch. 2025 Jan 13.

Combined exercise-induced modulation of Notch pathway and muscle quality in senescence-accelerated mice.

Ana P Pinto, Ângelo Augusto J Sarni, Maria Eduarda A Tavares, Alisson L da Rocha, Ruither O Gomes Carolino, Ivo V de Sousa Neto, Driele C Da Silva Ferreira, Vitor R Munoz, Giovana R Teixeira, Fernando M Simabuco, José R Pauli, Dennys E Cintra, Eduardo R Ropelle, Ellen C de Freitas, Adelino S R da Silva.

  The Notch signaling pathway is crucial for skeletal muscle development, regeneration, inflammation, and aging. This study investigated the association between interleukin-10 (IL-10) and the Notch pathway in C2C12 cells, as well as explored the effects of combined endurance and resistance exercise on the Notch and autophagy pathways in the skeletal muscle of senescence-accelerated mouse-resistant 1 Sedentary (SAMR1 CT), SAMR1 exercised (SAMR1 EX), senescence-accelerated prone mouse 8 Sedentary (SAMP8 CT), and SAMP8 exercised (SAMP8 EX). C2C12 myoblasts were transfected with siIL-10. Histological analysis, reverse transcription-quantitative polymerase chain reaction, and immunoblotting were performed on the quadriceps and tibialis anterior muscles. A publicly available dataset was analyzed to assess the Notch pathway in older men. In summary, IL-10 knockdown in myoblasts reduced the Notch pathway gene and protein expression. In SAMP8 mice, combined exercise improved muscle fiber organization, enhanced balance and coordination, and increased Notch2 and Hes1 mRNA levels. NOTCH2 mRNA levels were also higher in older men compared to young subjects with similar physical activity levels. These findings suggest that combined physical exercise enhances muscle regeneration via the Notch pathway in aged muscle.

Keywords:  Aging; Molecular pathway; Muscle development; Physical exercise

DOI:  https://doi.org/10.1007/s00424-024-03048-2
Funct Integr Genomics. 2025 Jan 15. 25(1): 14

Pan-cancer secreted proteome and skeletal muscle regulation: insight from a proteogenomic data-driven knowledge base.

Traci L Parry, L Anne Gilmore, Andy V Khamoui.

  Large-scale, pan-cancer analysis is enabled by data driven knowledge bases that link tumor molecular profiles with phenotypes. A debilitating cancer-related phenotype is skeletal muscle loss, or cachexia, which occurs partly from tumor products secreted into circulation. Using the LinkedOmicsKB knowledge base assembled from the Clinical Proteomics Tumor Analysis Consortium proteogenomic analysis, along with catalogs of human secretome proteins, ligand-receptor pairs and molecular signatures, we sought to identify candidate pan-cancer proteins secreted to blood that could regulate skeletal muscle phenotypes in multiple solid cancers. Tumor proteins having significant pan-cancer associations with muscle were referenced against secretome proteins secreted to blood from the Human Protein Atlas, then verified as increased in paired tumor vs. normal tissues in pan-cancer manner. This workflow revealed seven secreted proteins from cancers afflicting kidneys, head and neck, lungs and pancreas that classified as protein-binding activity modulator, extracellular matrix protein or intercellular signaling molecule. Concordance of these biomarkers with validated molecular signatures of cachexia and senescence supported relevance to muscle and cachexia disease biology, and high tumor expression of the biomarker set associated with lower overall survival. In this article, we discuss avenues by which skeletal muscle and cachexia may be regulated by these candidate pan-cancer proteins secreted to blood, and conceptualize a strategy that considers them collectively as a biomarker signature with potential for refinement by data analytics and radiogenomics for predictive testing of future risk in a non-invasive, blood-based panel amenable to broad uptake and early management.

Keywords:  CPTAC; Human protein atlas; LinkedOmicsKB; Muscle; Secretome; Tumor

DOI:  https://doi.org/10.1007/s10142-024-01524-7
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13677

The Effects of Glucagon-Like Peptide-1 Receptor Agonists on Mitochondrial Function Within Skeletal Muscle: A Systematic Review.

Victoria J Old, Melanie J Davies, Dimitris Papamargaritis, Pratik Choudhary, Emma L Watson.

   BACKGROUND: Obesity is a chronic disease associated with increased risk of multiple metabolic and mental health-related comorbidities. Recent advances in obesity pharmacotherapy, particularly with glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), have the potential to transform obesity and type 2 diabetes mellitus (T2DM) care by promoting marked weight loss, improving glycaemic control and addressing multiple obesity-related comorbidities, with added cardio-renal benefits. Dual agonists combining GLP-1 with other enteropancreatic hormones such as glucose-dependent insulinotropic polypeptide (GIP) have also been developed in recent years, leading to greater weight loss than using GLP-1 RAs alone. However, up to 40% of the weight lost with GLP-1 RAs comes from lean body mass, raising concerns about potential adverse effects on skeletal muscle function. Mitochondrial dysfunction, characterized by reduced mitochondrial size and activity, is prevalent in individuals with obesity and T2DM and is a known contributor to muscle wasting in ageing and some chronic diseases. This systematic review investigates the impact of GLP-1-based therapies on skeletal muscle mitochondrial function in individuals with obesity and T2DM or in related animal and cell models.
METHODS: A comprehensive search of MEDLINE, Scopus, CINAHL and clinicaltrials.gov was conducted. Inclusion criteria included randomized controlled trials, randomized crossover trials, cluster randomized control trials and basic science studies involving any GLP-1 RA or GLP-1/GIP dual agonist. Outcomes of interest were skeletal muscle respiratory function either in the form of measurements of mass, number, content, oxidative capacity/respiratory function, mitochondrial dynamics, mitochondrial biogenesis and mitophagy.
RESULTS: Eight studies were eligible for analysis; no human studies were identified. All of the included studies used GLP-1 RAs (single agonists) as intervention. The emerging evidence suggests that GLP-1 RAs increase mitochondrial area, number and morphology (i.e., reduces swelling). Data are conflicting on the effect of GLP-1 RAs upon mitochondrial mass, respiration and the expression of uncoupling proteins and PGC-1α. Data also demonstrate muscle specific (i.e., soleus vs. extensor digitorum longus) responses to GLP-1 RAs.
CONCLUSION: GLP-1 RAs appear to have a positive effect upon mitochondria area, number and morphology, but effects upon other aspects of mitochondrial health remain inconclusive. Data are very limited and solely presented in animal and in vitro models. Future studies should be conducted in human populations in order to begin to understand the effect of GLP-1 RAs and GLP-1-based therapies on human skeletal muscle mitochondria.

Keywords:  GLP‐1 RA; mitochondria; obesity; skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.13677
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13678

Iron Chelation Prevents Age-Related Skeletal Muscle Sarcopenia in Klotho Gene Mutant Mice, a Genetic Model of Aging.

Chhanda Bose, Judit Megyesi, Oleg Karaduta, Sharda P Singh, Sundararaman Swaminathan, Sudhir V Shah.

   BACKGROUND: A decline in skeletal muscle mass and function known as skeletal muscle sarcopenia is an inevitable consequence of aging. Sarcopenia is a major cause of decreased muscle strength, physical frailty and increased muscle fatigability, contributing significantly to an increased risk of physical disability and functional dependence among the elderly. There remains a significant need for a novel therapy that can improve sarcopenia and related problems in aging. Iron accumulation, especially catalytic iron (labile iron) through increased oxidative stress, could be one of the contributing factors to sarcopenia. Our study aimed to examine the effect of an iron chelator on age-related sarcopenia in mice.
METHODS: We investigated the effect of iron chelation (deferiprone, DFP) in sarcopenia, using mice with klotho deficiency (kl/kl), an established mouse model for aging. Four weeks old Klotho -/- male mice were treated with 25 mg/kg body weight of iron chelator deferiprone in drinking water for 8-14 weeks (n = 12/group, treated and untreated). At the end of the study, gastrocnemius, quadriceps and bicep muscles were dissected and used for western blot and immunohistochemistry analysis, histopathology and iron staining. Serum total iron, catalytic iron and cytokine ELISAs were performed with established methods.
RESULTS: Treatment with DFP significantly reduced loss of muscle mass in gastrocnemius and quadriceps muscles (p < 0.0001). Total and catalytic iron content of serum and iron in muscles were significantly (both p < 0.0001) lower in the treated animals. The inhibitory factor of myogenesis, the myostatin protein in gastrocnemius muscles (p = 0.019) and serum (p = 0.003) were downregulated after 8 weeks of therapy accompanied by an increased in muscle contractile protein myosin heavy chain (~2.9 folds, p = 0.0004). Treatment decreased inflammation (serum IL6 and TNFα) (p < 0.0001, p = 0.005), respectively, and elevated insulin-like growth factor levels (p = 0.472). This was associated with reduced DNA damage and reduced 8-hydroxy 2 deoxyguanosine in muscle and HO-1 protein (p < 0.001, p = 079), respectively. Significant weight loss (p < 0.001) and decreased water intake (p = 0.012) were observed in untreated mice compared to treatment group. Kaplan-Meier survival curves show the median life span of treated mice was 108 days as compared to 63 days for untreated mice (p = 0.0002).
CONCLUSIONS: In summary, our research findings indicate that deferiprone reduced age-related sarcopenia in the muscles of Klotho-/- mice. Our finding suggests chelation of excess iron could be an effective therapy to counter sarcopenia. However, additional studies are needed to evaluate and determine the efficacy in humans.

Keywords:  catalytic iron; deferiprone; klotho; myostatin; skeletal muscle sarcopenia

DOI:  https://doi.org/10.1002/jcsm.13678
Eur J Pharmacol. 2025 Jan 10. pii: S0014-2999(25)00018-4. [Epub ahead of print] 177265

Dehydroandrographolide Succinate Attenuates Dexamethasone-Induced Skeletal Muscle Atrophy by Regulating Akt/GSK3β and MuRF-1 Pathways.

Hengzhe Jin, Seo Hyoung Sig, Jinyoung Shin, Kyung-Jin Lee, Su Jung Kim, Seung Hyo Jung, Bokyung Kim.

  Andrographis paniculata (AGPA) is known for its wide-ranging biological activities, including antiviral, antipyretic, and anticancer properties. However, its effects on muscle atrophy have not been well understood. This study investigates the impact of andrographolide (AD) and dehydroandrographolide succinate (DAS), key components of AGPA, on skeletal muscle atrophy using in vitro and in vivo models. We employed dexamethasone (DEX)-treated mice and C2C12 myotubes as models of skeletal muscle atrophy. While DAS and AD did not reverse the DEX-induced reduction in body weight, both compounds significantly restored grip strength in DEX-treated mice. Notably, DAS treatment, but not AD, markedly improved running speed, endurance time, and distance. Both DAS and AD enhanced lean muscle mass in the whole body, tibialis anterior (TA), and gastrocnemius (GS) muscles, as well as increased TA thickness, with DAS demonstrating superior efficacy compared to AD. In C2C12 myotubes treated with DEX, DAS and AD increased ATP production and myotube diameter. Mechanistically, both compounds upregulated phosphorylation of Akt and GSK3β and downregulated MuRF-1 expression. These results indicate that DAS and AD mitigate muscle atrophy via the Akt/GSK3β and MuRF-1 pathways, with DAS showing greater anti-atrophy efficiency. Thus, DAS emerges as a promising therapeutic candidate for the prevention of skeletal muscle atrophy.

Keywords:  Akt; Andrographolide; Dehydroandrographolide succinate; GSK3β; MuRF-1; Skeletal muscle atrophy

DOI:  https://doi.org/10.1016/j.ejphar.2025.177265
PLoS One. 2025 ;20(1): e0317197

Protective effects of Lactobacillus plantarum strain against protein malnutrition-induced muscle atrophy and bone loss in juvenile mice.

Hyerim Park, Sung-Hee Kim, Kyung-Ah Lee.

Early-life malnutrition adversely affects nearly all organ systems, resulting in multiple physiological adaptations, including growth restriction and muscle and bone loss. Although there is growing evidence that probiotics effectively improve systemic growth under malnourished conditions in different animal models, our knowledge of the beneficial effects of probiotics on various organs is limited. Here, we show that Lactobacillus plantarum strain WJL (LpWJL) can mitigate skeletal muscle and bone loss in protein-malnourished juvenile mice. Mice on prenatal day 21 were fed a protein-malnourished (P-MAL) diet with or without LpWJL supplementation for six weeks. Compared to mice on the P-MAL diet alone, LpWJL supplementation significantly increased muscle mass and size, resulting in enhanced muscle strength and endurance capacity. Furthermore, LpWJL supplementation induced the expression of the key growth factor IGF-1 while decreasing muscle atrophy markers such as Atrogin-1 and MuRF-1, indicating potential mechanisms by which protein malnutrition-induced muscle wasting is counteracted. Additionally, LpWJL supplementation alleviated the reduction in cortical bone thickness and the deterioration of trabecular bone microstructure in the femur. Taken together, these results indicate that LpWJL can protect against skeletal muscle atrophy and compromised bone microarchitecture caused by protein malnutrition, providing novel insights into the potential therapeutic applications of probiotics for treating malnutrition-related disorders.

DOI: https://doi.org/10.1371/journal.pone.0317197
Acta Neuropathol Commun. 2025 Jan 16. 13(1): 11

Unraveling calcium dysregulation and autoimmunity in immune mediated rippling muscle disease.

Samir R Nath, Aneesha Dasgupta, Divyanshu Dubey, Eileen Kokesh, Grayson Beecher, Numrah Fadra, Teerin Liewuck, Sean Pittock, Jason D Doles, William Litchy, Margherita Milone.

  Rippling Muscle Disease (RMD) is a rare skeletal myopathy characterized by abnormal muscular excitability manifesting with wave-like muscle contractions and percussion-induced muscle mounding. Hereditary RMD is associated with caveolin-3 or cavin-1 mutations. Recently, we identified cavin 4 autoantibodies as a biomarker of immune-mediated RMD (iRMD), though the underlying disease-mechanisms remain poorly understood. Transcriptomic studies were performed on muscle biopsies of 8 patients (5 males; 3 females; ages 26-to-80) with iRMD. Subsequent pathway analysis compared iRMD to human non-disease control and disease control (dermatomyositis) muscle samples. Transcriptomic studies demonstrated changes in key pathways of muscle contraction and development. All iRMD samples had significantly upregulated cavin-4 expression compared to controls, likely compensatory for autoantibody-mediated protein degradation. Proteins involved in muscle relaxation (including SERCA1, PMCA and PLN) were significantly increased in iRMD compared to controls. Comparison of iRMD to dermatomyositis transcriptomics demonstrated significant overlap in immune pathways, and the IL-6 signaling pathway was markedly increased in all iRMD patient muscle biopsies and increased in the majority of iRMD patients' serum. This study represents the first muscle transcriptomic analysis of iRMD patients and dissects underlying disease mechanisms. Increase of sarcolemmal and cellular calcium channels as well as PLN, an inhibitor of the SERCA pump for calcium into the sarcoplasm, likely alters the calcium dynamics in iRMD. These changes in crucial components of muscle relaxation may underlie rippling by altering calcium flux. Our findings provide crucial insights into the differential expression of genes regulating muscle relaxation and highlight potential disease pathomechanisms.

Keywords:  Immune mediated rippling muscle disease; Interferon; Interleukin-6; Myopathy; Transcriptomics

DOI:  https://doi.org/10.1186/s40478-025-01926-z
BMC Genomics. 2025 Jan 13. 26(1): 29

Unravelling the transcriptomic symphony of muscle ageing: key pathways and hub genes altered by ageing and caloric restriction in rat muscle revealed by RNA sequencing.

Gulam Altab, Brian J Merry, Charles W Beckett, Priyanka Raina, Inês Lopes, Katarzyna Goljanek-Whysall, João Pedro de Magalhães.

  Age-related muscle wasting, sarcopenia is an extensive loss of muscle mass and strength with age and a major cause of disability and accidents in the elderly. Mechanisms purported to be involved in muscle ageing and sarcopenia are numerous but poorly understood, necessitating deeper study. Hence, we employed high-throughput RNA sequencing to survey the global changes in protein-coding gene expression occurring in skeletal muscle with age. Caloric restriction (CR) is a known prophylactic intervention against sarcopenia. Therefore, total RNA was isolated from the muscle tissue of both rats fed ad libitum and CR rats. RNA-seq data were subjected to Gene Ontology, pathway, co-expression, and interaction network analyses. This revealed the functional pathways most activated by both ageing and CR, as well as the key "hub" proteins involved in their activation.RNA-seq revealed 442 protein-coding genes to be upregulated and 377 to be downregulated in aged muscle, compared to young muscle. Upregulated genes were commonly involved in protein folding and immune responses; meanwhile, downregulated genes were often related to developmental biology. CR was found to suppress 69.7% and rescue 57.8% of the genes found to be upregulated and downregulated in aged muscle, respectively. In addition, CR uniquely upregulated 291 and downregulated 304 protein-coding genes. Hub genes implicated in both ageing and CR included Gc, Plg, Irf7, Ifit3, Usp18, Rsad2, Blm and RT1-A2, whilst those exclusively implicated in CR responses included Alb, Apoa1, Ambp, F2, Apoh, Orm1, Mx1, Oasl2 and Rtp4. Hub genes involved in ageing but unaffected by CR included Fgg, Fga, Fgb and Serpinc1. In conclusion, this comprehensive RNA sequencing study highlights gene expression patterns, hub genes and signalling pathways most affected by ageing in skeletal muscle. This data may provide the initial evidence for several targets for potential future therapeutic interventions against sarcopenia.

Keywords:  Diet; Functional genomics; Nutrigenomics; Sarcopenia

DOI:  https://doi.org/10.1186/s12864-024-11051-1
FASEB J. 2025 Jan 31. 39(2): e70325

Ablation of satellite cell-specific clock gene, Bmal1, alters force production, muscle damage, and repair following contractile-induced injury.

Ryan E Kahn, Pei Zhu, Ishan Roy, Clara Peek, John A Hawley, Sudarshan Dayanidhi.

  Following injury, skeletal muscle undergoes repair via satellite cell (SC)-mediated myogenic progression. In SCs, the circadian molecular clock gene, Bmal1, is necessary for appropriate myogenic progression and repair with evidence that muscle molecular clocks can also affect force production. Utilizing a mouse model allowing for inducible depletion of Bmal1 within SCs, we determined contractile function, SC myogenic progression and muscle damage and repair following eccentric contractile-induced injury. At baseline, SC-Bmal1iKO animals exhibited a ~20-25% reduction in normalized force production (ex vivo and in vivo) versus control SC-Bmal1Cntrl and SC-Bmal1iKO untreated littermates (p < .05). Following contractile injury, SC-Bmal1iKO animals displayed reduced muscle damage and subsequent repair post-injury (Dystrophinnegative fibers 24 h: SC-Bmal1Cntrl 199 ± 41; SC-Bmal1iKO 36 ± 13, p < .05) (eMHC+ fibers 7 day: SC-Bmal1Cntrl 217.8 ± 115.5; SC-Bmal1iKO 27.8 ± 17.3; Centralized nuclei 7 day: SC-Bmal1Cntrl 160.7 ± 70.5; SC-Bmal1iKO 46.2 ± 15.7). SC-Bmal1iKO animals also showed reduced neutrophil infiltration, consistent with less injury (Neutrophil content 24 h: SC-Bmal1Cntrl 2.4 ± 0.4; SC-Bmal1iKO 0.4 ± 0.2, % area fraction, p < .05). SC-Bmal1iKO animals had greater SC activation/proliferation at an earlier timepoint (p < .05) and an unexplained increase in activation 7 days post injury. Collectively, these data suggest SC-Bmal1 plays a regulatory role in force production, influencing the magnitude of muscle damage/repair, with an altered SC myogenic progression following contractile-induced muscle injury.

Keywords:  contractile injury; force production; molecular clocks; muscle repair; muscle stem cells; myogenic progression

DOI:  https://doi.org/10.1096/fj.202402145RR
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13668

Local Inflammation Precedes Diaphragm Wasting and Fibrotic Remodelling in a Mouse Model of Pancreatic Cancer.

Daria Neyroud, Andrew C D'Lugos, Enrique J Trevino, Chandler S Callaway, Jacqueline Lamm, Orlando Laitano, Brittney Poole, Michael R Deyhle, Justina Brantley, Lam Le, Andrew R Judge, Sarah M Judge.

   BACKGROUND: Cancer cachexia represents a debilitating muscle wasting condition that is highly prevalent in gastrointestinal cancers, including pancreatic ductal adenocarcinoma (PDAC). Cachexia is estimated to contribute to ~30% of cancer-related deaths, with deterioration of respiratory muscles suspected to be a key contributor to cachexia-associated morbidity and mortality. In recent studies, we identified fibrotic remodelling of respiratory accessory muscles as a key feature of human PDAC cachexia.
METHODS: To gain insight into mechanisms driving respiratory muscle wasting and fibrotic remodelling in response to PDAC, we conducted temporal histological and transcriptomic analyses on diaphragm muscles harvested from mice-bearing orthotopic murine pancreatic (KPC) tumours at time points reflective of precachexia (D8 and D10), mild-moderate cachexia (D12 and D14) and advanced cachexia (endpoint).
RESULTS: During the precachexia phase, diaphragms showed significant leukocyte infiltration (+3-fold to +13-fold; D8-endpoint vs. Sham, p < 0.05) and transcriptomic enrichment of inflammatory processes associated with tissue injury that remained increased through endpoint. Diaphragm inflammation was followed by increases in PDGFR-ɑ+ fibroadipogenic progenitors (+2.5 to +3.8-fold; D10-endpoint vs. Sham, p < 0.05), fibre atrophy (-16% to -24%, D12 to endpoint vs. Sham, p < 0.05), ECM expansion (+1.5 to +1.8-fold; D14-endpoint vs. Sham, p < 0.05), collagen accumulation (+3.8-fold; endpoint vs. Sham, p = 0.0013) and reductions in breathing frequency (-55%, p = 0.0074) and diaphragm excursion (-43%, p = 0.0006). These biological processes were supported by changes in the diaphragm transcriptome. Ingenuity pathway analysis predicted factors involved in inflammatory responses to tissue injury, including TGF-β1, angiotensin and PDGF BB, as top upstream regulators activated in diaphragms prior to and throughout cachexia progression, while PGC-1α and the insulin receptor were among the top upstream regulators predicted to be suppressed. The transcriptomic dataset further revealed progressive disturbances to networks involved in lipid, glucose and oxidative metabolism, activation of the unfolded protein response and neuromuscular junction remodelling associated with denervation.
CONCLUSIONS: In summary, our data support leukocyte infiltration and expansion of PDGFRα mesenchymal progenitors as early events that precede wasting and fibrotic remodelling of the diaphragm in response to PDAC that may also underlie metabolic disturbances, weakness and respiratory complications.

Keywords:  cancer cachexia; inflammatory response; muscle atrophy; muscle fibrosis; pancreatic cancer

DOI:  https://doi.org/10.1002/jcsm.13668
Neuropathol Appl Neurobiol. 2025 Feb;51(1): e70000

A Homozygous ATP2A2 Variant Alters Sarcoendoplasmic Reticulum Ca2+-ATPase 2 Function in Skeletal Muscle and Causes a Novel Vacuolar Myopathy.

Laura Llansó, Gianina Ravenscroft, Cristina Aceituno, Antonio Gutiérrez, Jevin Parmar, Pia Gallano, Marta Caballero-Ávila, Álvaro Carbayo, Ana Vesperinas, Roger Collet, Rosa Blanco, Nigel Laing, Leif Hove-Madsen, Eduard Gallardo, Montse Olivé.

   AIMS: Sarcoendoplasmic reticulum Ca2+-ATPase 2 (SERCA2), encoded by ATP2A2, is a key protein involved in intracellular Ca2+ homeostasis. The SERCA2a isoform is predominantly expressed in cardiomyocytes and type I myofibres. Variants in this gene are related to Darier disease, an autosomal dominant dermatologic disorder, but have never been linked to myopathy. We describe four patients suffering from a novel myopathy caused by a homozygous missense variant in ATP2A2.
METHODS: We studied a family with four individuals suffering from an adult-onset skeletal myopathy. We evaluated the clinicopathological phenotype, muscle imaging, and genetic workup including whole genome sequencing and segregation analysis. SERCA2 expression in skeletal muscle was assessed. Functional studies to evaluate Ca2+ handling in patient myotubes in response to electrical stimulation or caffeine exposure were performed.
RESULTS: Four sisters developed slowly progressive proximal weakness in adulthood. Biopsy findings showed small vacuoles restricted to type I myofibres. Ultrastructural analysis showed sarcotubular dilation and autophagic vacuoles. Genome sequencing revealed a homozygous variant in ATP2A2 (c.1117G > A, p.(Glu373Lys)) which segregated with the disease. Immunohistochemistry suggested that there was SERCA2 mislocalisation in patient myofibres. Western blotting did not show changes in the amount of protein. In vitro functional studies revealed delayed sarcoendoplasmic reticulum Ca2+ reuptake in patient myotubes, consistent with an altered pumping capacity of SERCA2 after cell stimulation.
CONCLUSIONS: We report a novel adult-onset vacuolar myopathy caused by a homozygous variant in ATP2A2. Biopsy findings and functional studies demonstrating an impaired function of SERCA2 and consequent Ca2+ dysregulation in slow-twitch skeletal myofibres highly support the pathogenicity of the variant.

Keywords:   ATP2A2 ; Darier disease (DD); sarcoendoplasmic reticulum (SR); sarcoendoplasmic reticulum Ca2+‐ATPase (SERCA); sarcotubular myopathy; vacuolar myopathy; western blot (WB); whole genome sequencing (WGS)

DOI:  https://doi.org/10.1111/nan.70000
J Physiol. 2025 Jan 13.

Heat boost: therapeutic approach for skeletal muscle health and postprandial mechanisms in older adults.

Marcos S Keefe, Mario I Hernandez, Alexandra P Brojanac, Kelly B Elliott, Ruben E Moya, Ryan A Dunn.



Keywords:  older adults; passive heat therapy; skeletal muscle

DOI:  https://doi.org/10.1113/JP287837
JACC Basic Transl Sci. 2024 Dec;9(12): 1426-1428

Mechanisms of Skeletal Muscle Dysfunction in Cardiometabolic HFpEF and Its Reversal With Exercise Training.

Bharathi Upadhya, Dalane W Kitzman.



Keywords:  branched-chained amino acids; exercise; heart failure with preserved ejection fraction; metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.jacbts.2024.10.009
STAR Protoc. 2025 Jan 10. pii: S2666-1667(24)00714-7. [Epub ahead of print]6(1): 103549

Protocol for the three-dimensional analysis of rodent skeletal muscle.

Smrithi Karthikeyan, Yoko Asakura, Mayank Verma, Atsushi Asakura.

  Confocal imaging is a powerful tool capable of analyzing cellular spatial data within a given tissue. Here, we present a protocol for preparing optically cleared extensor digitorum longus (EDL) skeletal muscle samples suitable for confocal imaging/computational analysis. We describe steps for sample preparation (including perfusion fixation and tissue clearing of muscle samples), image acquisition, and computational analysis, with sample segmentation/3D rendering outlined. This protocol can be applied to characterize various cell types, including muscle satellite cells (muscle stem cells) and capillary endothelial cells within rodent skeletal muscle. For complete details on the use and execution of this protocol, please refer to Verma et al.,1 Verma et al.,2 Karthikeyan et al.,3 and Karthikeyan et al.4.

Keywords:  cell differentiation; classification Description: cell biology; developmental biology; model organisms; molecular biology; stem cells

DOI:  https://doi.org/10.1016/j.xpro.2024.103549
Nat Commun. 2025 Jan 10. 16(1): 577

Aptamer-conjugated gold nanoparticles enable oligonucleotide delivery into muscle stem cells to promote regeneration of dystrophic muscles.

Francesco Millozzi, Paula Milán-Rois, Arghya Sett, Giovanni Delli Carpini, Marco De Bardi, Miguel Gisbert-Garzarán, Martina Sandonà, Ciro Rodríguez-Díaz, Mario Martínez-Mingo, Irene Pardo, Federica Esposito, Maria Teresa Viscomi, Marina Bouché, Ornella Parolini, Valentina Saccone, Jean-Jacques Toulmé, Álvaro Somoza, Daniela Palacios.

Inefficient targeting of muscle stem cells (MuSCs), also called satellite cells, represents a major bottleneck of current therapeutic strategies for muscular dystrophies, as it precludes the possibility of promoting compensatory regeneration. Here we describe a muscle-targeting delivery platform, based on gold nanoparticles, that enables the release of therapeutic oligonucleotides into MuSCs. We demonstrate that AuNPs conjugation to an aptamer against α7/β1 integrin dimers directs either local or systemic delivery of microRNA-206 to MuSCs, thereby promoting muscle regeneration and improving muscle functionality, in a mouse model of Duchenne Muscular Dystrophy. We show here that this platform is biocompatible, non-toxic, and non-immunogenic, and it can be easily adapted for the release of a wide range of therapeutic oligonucleotides into diseased muscles.

DOI: https://doi.org/10.1038/s41467-024-55223-9
Exerc Sport Sci Rev. 2025 Jan 13.

Focus on the Forgotten Organelle: Regulation of Lysosomes in Skeletal Muscle.

Neushaw Moradi, Anastasiya Kuznyetsova, Victoria C Sanfrancesco, Sabrina Champsi, David A Hood.

ABSTRACT: Research on the role of the lysosome as the terminal organelle in autophagy and in communicating with other organelles in skeletal muscle is in its infancy. We hypothesize that the lysosome can adapt positively to exercise to improve the clearance of cargo, like dysfunctional mitochondria, within muscle, representing an important therapy for protein homeostasis in aging and muscle disuse.

DOI: https://doi.org/10.1249/JES.0000000000000358
Int J Mol Sci. 2025 Jan 06. pii: 414. [Epub ahead of print]26(1):

Role of PI3 Kinases in Cell Signaling and Soleus Muscle Atrophy During Three Days of Unloading.

Ksenia A Zaripova, Svetlana P Belova, Tatiana Y Kostrominova, Boris S Shenkman, Tatiana L Nemirovskaya.

  During skeletal muscle unloading, phosphoinositide 3-kinase (PI3K), and especially PI3K gamma (PI3Kγ), can be activated by changes in membrane potential. Activated IP3 can increase the ability of Ca2+ to enter the nucleus through IP3 receptors. This may contribute to the activation of transcription factors that initiate muscle atrophy processes. LY294002 inhibitor was used to study the role of PI3K in the ATP-dependent regulation of skeletal muscle signaling during three days of unloading. Inhibition of PI3K during soleus muscle unloading slows down the atrophic processes and prevents the accumulation of ATP and the expression of the E3 ubiquitin ligase MuRF1 and ubiquitin. It also prevents the increase in the expression of IP3 receptors and regulates the activity of Ca2+-dependent signaling pathways by reducing the mRNA expression of the Ca2+-dependent marker calcineurin (CaN) and decreasing the phosphorylation of CaMKII. It also affects the regulation of markers of anabolic signaling in unloaded muscles: IRS1 and 4E-BP. PI3K is an important mediator of skeletal muscle atrophy during unloading. Developing strategies for the localized skeletal muscle release of PI3K inhibitors might be one of the future treatments for inactivity and disease-induced muscle atrophy.

Keywords:  ATP; MuRF1; PI3 kinase; muscle atrophy; unloading

DOI:  https://doi.org/10.3390/ijms26010414
Sci Rep. 2025 Jan 13. 15(1): 1778

Titin fragment is a sensitive biomarker in Duchenne muscular dystrophy model mice carrying full-length human dystrophin gene on human artificial chromosome.

Yosuke Hiramuki, Miwa Hosokawa, Kayo Osawa, Taku Shirakawa, Yasuhiro Watanabe, Ritsuko Hanajima, Hiroyuki Kugoh, Hiroyuki Awano, Masafumi Matsuo, Yasuhiro Kazuki.

  Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations of the dystrophin gene, which spans 2.4 Mb on the X chromosome. Creatine kinase (CK) activity in blood and titin fragment levels in urine have been identified as biomarkers in DMD to monitor disease progression and evaluate therapeutic intervention. However, the difference in the sensitivity of these biomarkers in DMD remains unclear. Previously, we generated transchromosomic mice carrying the full-length human dystrophin gene on a human artificial chromosome (DYS-HAC1) vector. The human dystrophin derived from DYS-HAC1 improved pathological phenotypes observed in DMD-null mice, which lack the entire 2.4 Mb of the dystrophin gene. In this study, we compared the values of plasma CK activity and urine/plasma titin fragment levels in wild-type (WT), DYS-HAC1, DMD-null, and DYS-HAC1; DMD-null mice. Plasma CK activity and urine/plasma titin fragment levels in DMD-null mice were significantly higher than those in WT mice. Although plasma CK activity showed no significant difference between WT and DYS-HAC1; DMD-null mice, urine/plasma titin fragment levels in DYS-HAC1; DMD-null mice were higher than those in WT mice. Human dystrophin in DYS-HAC1; DMD-null mice drastically improved muscular dystrophy phenotypes seen in DMD-null mice; however, the proportion of myofibers with central nuclei in DYS-HAC1; DMD-null mice had a tendency to be slightly higher than that in WT mice. These results suggest that urine/plasma titin fragment levels could be a more sensitive biomarker than plasma CK activity.

Keywords:  Creatine kinase; Duchenne muscular dystrophy; Dystrophin; Human artificial chromosome; Titin

DOI:  https://doi.org/10.1038/s41598-025-85369-5
Physiol Rep. 2025 Jan;13(2): e70170

Effects of defined voluntary running distances coupled with high-fat diet consumption on the skeletal muscle transcriptome of male mice.

Afrina Brishti, Sarah J Johnson, Daniel G Palmer, Md Obayed Raihan, Lin Yan, Shanon L Casperson.

  Exercise counters many adverse health effects of consuming a high-fat diet (HFD). However, complex molecular changes that occur in skeletal muscle in response to exercising while consuming a HFD are not yet known. We investigated the interplay between diverse exercise regimes and HFD consumption on the adaptation of skeletal muscle transcriptome. C57BL/6 male mice were randomized into five groups-one sedentary control group and four exercise groups. The exercise groups consisted of an unrestricted running group (8.3 km/day) and three groups that were restricted to 75%, 50%, or 25% of unrestricted running (6.3, 4.2, and 2.1 km/day, respectively). Total RNA was extracted from frozen gastrocnemius muscle for transcriptome analyses. DEG counts were 1347, 1823, 1103, and 1107 and there were 107, 169, 67, and 89 unique genes present in the HFD-25%, HFD-50%, HFD-75%, and HFD-U, respectively. Comparing exercise groups, we found that exercising at 50% resulted in the most differentially expressed transcripts with the MAPK and PPAR signaling pathways enriched in down- and up-regulated genes, respectively. These results demonstrate that running distance impacts the adaptation of the skeletal muscle transcriptome to exercise and suggest that middle-distance running may provide the greatest protection against high-fat diet-induced stress coupled with exercise.

Keywords:  high‐fat diet; skeletal muscle; transcriptome; voluntary exercise

DOI:  https://doi.org/10.14814/phy2.70170
Skelet Muscle. 2025 Jan 13. 15(1): 2

Aminoguanidine hemisulfate improves mitochondrial autophagy, oxidative stress, and muscle force in Duchenne muscular dystrophy via the AKT/FOXO1 pathway in mdx mice.

Shiyue Sun, Tongtong Yu, Joo Young Huh, Yujie Cai, Somy Yoon, Hafiz Muhammad Ahmad Javaid.

   BACKGROUND: Duchenne muscular dystrophy (DMD) is a prevalent, fatal degenerative muscle disease with no effective treatments. Mdx mouse model of DMD exhibits impaired muscle performance, oxidative stress, and dysfunctional autophagy. Although antioxidant treatments may improve the mdx phenotype, the precise molecular mechanisms remain unclear. This study investigates the effects of aminoguanidine hemisulfate (AGH), an inhibitor of reactive oxygen species (ROS), on mitochondrial autophagy, oxidative stress, and muscle force in mdx mice.
METHODS: Male wild-type (WT) and mdx mice were divided into three groups: WT, mdx, and AGH-treated mdx mice (40 mg/kg intraperitoneally for two weeks) at 6 weeks of age. Gene expression, western blotting, H&E staining, immunofluorescence, ROS assays, TUNEL apoptosis, glutathione activity, and muscle force measurements were performed. Statistical comparisons used one-way ANOVA.
RESULTS: AGH treatment significantly reduced the protein levels of LC3, and p62 in mdx mice, indicating improved autophagy activity and the ability to clear damaged mitochondria. AGH restored the expression of mitophagy-related genes Pink1 and Parkin and increased Mfn1, rebalancing mitochondrial dynamics. It also increased Pgc1α and mtTFA levels, promoting mitochondrial biogenesis. ROS levels were reduced, with higher Prdx3 and MnSOD expression, improving mitochondrial antioxidant defenses. AGH normalized the GSSG/GSH ratio and decreased glutathione reductase and peroxidase activities, further improving redox homeostasis. Additionally, AGH reduced apoptosis, shown by fewer TUNEL-positive cells and lower caspase-3 expression. Histological analysis revealed decreased muscle damage and fewer embryonic and neonatal myosin-expressing fibers. AGH altered fiber composition, decreasing MyH7 while increasing MyH4 and MyH2. Muscle force improved significantly, with greater twitch and tetanic forces. Mechanistically, AGH modulated the AKT/FOXO1 pathway, decreasing myogenin and Foxo1 while increasing MyoD.
CONCLUSIONS: AGH treatment restored mitochondrial autophagy, reduced oxidative stress, apoptosis, and altered muscle fiber composition via the AKT/FOXO1 pathway, collectively improving muscle force in mdx mice. We propose AGH as a potential therapeutic strategy for DMD and related muscle disorders.

Keywords:   Mdx ; Aminoguanidine; Apoptosis; Autophagy; DMD; Mitochondria; ROS

DOI:  https://doi.org/10.1186/s13395-024-00371-1
J Clin Invest. 2025 Jan 14. pii: e176942. [Epub ahead of print]

Impaired hydrogen sulfide biosynthesis underlies eccentric contraction-induced force loss in dystrophin-deficient skeletal muscle.

W Michael Southern, Erynn E Johnson, Elizabeth K Fasbender, Katherine S Fallon, Courtney L Cavazos, Dawn A Lowe, George G Rodney, James M Ervasti.

  Eccentric contraction- (ECC) induced force loss is a hallmark of murine dystrophin-deficient (mdx) skeletal muscle that is used to assess efficacy of potential therapies for Duchenne muscular dystrophy. While virtually all key proteins involved in muscle contraction have been implicated in ECC force loss, a unifying mechanism that orchestrates force loss across such diverse molecular targets has not been identified. We showed that correcting defective hydrogen sulfide (H2S) signaling in mdx muscle prevented ECC force loss. We also showed that the cysteine proteome of skeletal muscle functioned as a redox buffer in WT and mdx muscle during ECCs, but that buffer capacity in mdx muscle was significantly compromised by elevated basal protein oxidation. Finally, chemo-proteomic data suggested that H2S protected several proteins central to muscle contraction against irreversible oxidation through persulfidation-based priming. Our results support a unifying, redox-based mechanism of ECC force loss in mdx muscle.

Keywords:  Metabolism; Muscle biology; Neuromuscular disease; Proteomics; Skeletal muscle

DOI:  https://doi.org/10.1172/JCI176942
Curr Res Physiol. 2025 ;8 100138

From molecular to physical function: The aging trajectory.

Tom A H Janssen, Caroline V Lowisz, Stuart Phillips.

  Aging is accompanied by a decline in muscle mass, strength, and physical function, a condition known as sarcopenia. Muscle disuse attributed to decreased physical activity, hospitalization, or illness (e.g. sarcopenia) results in a rapid decline in muscle mass in aging individuals and effectively accelerates sarcopenia. Consuming protein at levels above (at least 50-100% higher) the current recommended intakes of ∼0.8 g protein/kg bodyweight/d, along with participating in both resistance and aerobic exercise, will aid in the preservation of muscle mass. Physiological muscle adaptations often accompany the observable changes in physical independence an older adult undergoes. Muscle fibre adaptations include a reduction in type 2 fibre size and number, a loss of motor units, reduced sensitivity to calcium, reduced elasticity, and weak cross-bridges. Mitochondrial function and structure are impaired in relation to aging and are worsened with inactivity and disease states but could be overcome by engaging in exercise. Intramuscular connective tissue adaptations with age are evident in animal models; however, the adaptations in collagenous tissue within human aging are less clear. We know that the satellite muscle cell pool decreases with age, and there is a reduced capacity for muscle repair/regeneration. Finally, a pro-inflammatory state associated with age has detrimental impacts on the muscle. The purpose of this review is to highlight the physiological adaptations driving muscle aging and their potential mitigation with exercise/physical activity and nutrition.

Keywords:  Atrophy; Exercise; Inflammaging; Nutrition; Protein; Sarcopenia; Skeletal muscle physiology

DOI:  https://doi.org/10.1016/j.crphys.2024.100138