bims-moremu 2025-03-02 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–03–02
thirty papers selected by
Anna Vainshtein, Craft Science Inc.

High-intensity interval training alleviates STZ-induced muscle atrophy by restoration of nuclear positioning defects in C57BL/6 male mice.
Resistance exercise training in older men reduces ATF4-activated and senescence-associated mRNAs in skeletal muscle.
Identification of a senescence-associated transcriptional program in skeletal muscle of cachectic pancreatic-tumor bearing mice.
Nuclear Factor κB Signaling Revisited: Its Role in Skeletal Muscle and Exercise.
ActRII or BMPR ligands inhibit skeletal myoblast differentiation, and BMPs promote heterotopic ossification in skeletal muscles in mice.
Transcriptomic adaptation of skeletal muscle in response to MICT and HIIT exercise modalities.
Stress exposure in the mdx mouse model of Duchenne muscular dystrophy provokes a widespread metabolic response.
Soluble RAGE enhances muscle regeneration after cryoinjury in aged and diseased mice.
Rebastinib inhibits FoxO1 activity and reduces dexamethasone-induced atrophy and its-related gene expression in cultured myotubes.
CLIC5 promotes myoblast differentiation and skeletal muscle regeneration via the BGN-mediated canonical Wnt/β-catenin signaling pathway.
Effects of Physical Exercise on MuRF-1/TRIM63 mRNA Expression in Humans: A Systematic Review.
Oral contraceptive pill phase does not influence muscle protein synthesis or myofibrillar proteolysis at rest or in response to resistance exercise.
NE-MTOC Formation in Skeletal Muscle Is Mbnl2-Dependent and Occurs in a Sequential and Gradual Manner.
A framework of biomarkers for skeletal muscle aging: a consensus statement by the Aging Biomarker Consortium.
Bone and muscle crosstalk in ageing and disease.
Withaferin A Attenuates Muscle Cachexia Induced by Angiotensin II Through Regulating Pathways Activated by Angiotensin II.
ADAMTS4 Reduction Contributes to Extracellular Matrix Deposition and Impaired Myogenesis in the Skeletal Muscle of Cigarette Smoke-Exposed Mice.
Cigarette Smoking Induces Skeletal Muscle Atrophy in Mice by Activated Macrophage-Mediated Pyroptosis.
Dietary nitrate supplementation mitigates age-related changes at the neuromuscular junction in mice.
Low-Carbohydrate Diet Exacerbates Denervation-Induced Atrophy of Rat Skeletal Muscle Under the Condition of Identical Protein Intake.
Human iPSC-Derived Muscle Cells as a New Model for Investigation of EDMD1 Pathogenesis.
Optimizing Electrical Field Stimulation Parameters Reveals the Maximum Contractile Function of Human Skeletal Muscle Microtissues.
Evolutionary Insights into Irisin/FNDC5: Roles in Aging and Disease from Drosophila to Mammals.
GL261 glioblastoma induces delayed body weight gain and stunted skeletal muscle growth in young mice.
Aging-related hyperphosphatemia triggers the release of TNF-α from macrophages, promoting indicators of sarcopenia through the reduction of IL-15 expression in skeletal muscle.
Structural insights into transmembrane helix S0 facilitated RyR1 channel gating by Ca2+/ATP.
Alterations of PINK1-PRKN signaling in mice during normal aging.
Leptin enhances the intracellular thyroid hormone activation in skeletal muscle to boost energy balance.
Divergent Multiomic Acute Exercise Responses Reveal the Impact of Sex as a Biological Variable.
Enzymatic Isolation of Skeletal Muscle Interstitial Extracellular Vesicles.

Sci Rep. 2025 Feb 26. 15(1): 6891

High-intensity interval training alleviates STZ-induced muscle atrophy by restoration of nuclear positioning defects in C57BL/6 male mice.

Masoud Rahmati, Rohollah Nikooie.

  We tested the hypothesis that improper myonuclei arrangement and morphology are involved in diabetes-induced myofiber atrophy and whether and how high-intensity interval training (HIIT) affects these impairments in isolated skeletal muscle myofibers. STZ-induced diabetes decreased muscle fiber cross-sectional area (CSA) mediated by reduced myonuclear number, enhanced nuclear apoptotic, and failed nuclear accretion from satellite cells. STZ-induced muscle atrophy was accompanied by improper nuclear positioning (sinus of the maximum diameter angles and distance between adjacent myonuclei) and morphology (maximum diameter, area, and volume of the nuclei), which was mediated by suppressed expression of proteins involved in nuclear positioning including KIF5B, dynein, and Nesprin1. Disturbing nuclear positioning by inhibition of Kinsein1 activity reduced CSA to a greater extent than in diabetes alone, suggesting STZ-induced muscle atrophy is mediated by changes in nuclear positioning. HIIT alleviated the STZ-induced decline in muscle CSA and myonuclei per fiber by restoring myonuclear morphometry impairments and improper nuclear positioning to the normal level. HIIT-induced increase in muscle CSA deterred by inhibition of Kinesin1 activity, suggesting its effect is mediated by proper nuclear positioning. These findings suggest that normal nuclear positioning are required for the changes in fiber size properties associated with HIIT in diabetic skeletal muscle fibers.

Keywords:  Diabetic myopathy; High-intensity interval training; Hypertrophy; Kinesin-1; Nuclear movement

DOI:  https://doi.org/10.1038/s41598-025-91259-7
Geroscience. 2025 Feb 27.

Resistance exercise training in older men reduces ATF4-activated and senescence-associated mRNAs in skeletal muscle.

Zachary D Von Ruff, Matthew J Miller, Tatiana Moro, Paul T Reidy, Scott M Ebert, Elena Volpi, Christopher M Adams, Blake B Rasmussen.

  Sarcopenia increases the risk of frailty, morbidity, and mortality in older adults. Resistance exercise training improves muscle size and function; however, the response to exercise training is variable in older adults. The objective of our study was to determine both the age-independent and age-dependent changes to the transcriptome following progressive resistance exercise training. Skeletal muscle biopsies were obtained before and after 12 weeks of resistance exercise training in 8 young (24 ± 3.3 years) and 10 older (72 ± 4.9 years) men. RNA was extracted from each biopsy and prepared for analysis via RNA sequencing. We performed differential mRNA expression, gene ontology, and gene set enrichment analyses. We report that when comparing post-training vs pre-training 226 mRNAs and 959 mRNAs were differentially expressed in the skeletal muscle of young and older men, respectively. Additionally, 94 mRNAs increased, and 17 mRNAs decreased in both young and old, indicating limited overlap in response to resistance exercise training. Furthermore, the differential gene expression was larger in older skeletal muscle. Finally, we report three novel findings: 1) resistance exercise training decreased the abundance of ATF4-activated and senescence-associated skeletal muscle mRNAs in older men; 2) resistance exercise-induced increases in lean mass correlate with increased mRNAs encoding mitochondrial proteins; and 3) increases in muscle strength following resistance exercise positively correlate with increased mRNAs involved in translation, rRNA processing, and polyamine metabolism. We conclude that resistance exercise training elicits a differential gene expression response in young and old skeletal muscle, including reduced ATF-4 activated and senescence-associated gene expression.

Keywords:  ATF4; Aging; Resistance exercise; Senescence; Skeletal muscle

DOI:  https://doi.org/10.1007/s11357-025-01564-2
Am J Physiol Cell Physiol. 2025 Feb 24.

Identification of a senescence-associated transcriptional program in skeletal muscle of cachectic pancreatic-tumor bearing mice.

Jeremy B Ducharme, Madison E Carelock, Martin M Schonk, Nour M Al-Zaeed, Weizhou Zhang, Sarah M Judge, Andrew R Judge.

  Cancer cachexia is the involuntary loss of body and skeletal muscle mass, which negatively impacts physical function, quality of life, treatment tolerance, and survival. Skeletal muscles of cachectic people and mice with pancreatic tumors also exhibit skeletal muscle damage, non-resolute immune cell infiltration, and impaired regeneration. These phenotypes may be influenced by the accumulation of senescent cells, which secrete factors detrimental to skeletal muscle health. However, there is currently no comprehensive research on senescent cell accumulation in skeletal muscle of tumor-bearing hosts, with or without chemotherapy. To address this gap, we cross-referenced the SenMayo panel of 125 senescence-related genes with our RNA-seq dataset in mouse skeletal muscle during the initiation and progression of cancer cachexia, which revealed a differential expression of 39 genes at pre-cachexia, 64 genes at cachexia onset, and 72 genes when cachexia is severe. Since p16 is a canonical marker of senescence, we subsequently orthotopically injected p16-tdTomato reporter mice with murine KPC pancreatic cancer cells and treated a subset of mice with chemotherapy. At experimental endpoint, when KPC treatment-naïve mice were cachectic, we observed an increased accumulation of p16+ cells, along with increased mRNA levels of hallmark senescence markers (Cdkn1a/p21, Cdkn2a/p16, Glb1/senescent-associated-β-galactosidase), which were exacerbated by chemotherapy. Lastly, we demonstrate an increase in CDKN1A/p21 in the muscle of cachectic patients with pancreatic cancer, which associated with cachexia severity. These findings suggest that senescent cells accumulate in skeletal muscle of cachectic pancreatic tumor-bearing hosts and that chemotherapy can exacerbate this accumulation.

Keywords:  Cachexia; Cellular Senescence; Glb1; p16; p21

DOI:  https://doi.org/10.1152/ajpcell.00816.2024
Free Radic Biol Med. 2025 Feb 24. pii: S0891-5849(25)00088-7. [Epub ahead of print]

Nuclear Factor κB Signaling Revisited: Its Role in Skeletal Muscle and Exercise.

Li Li Ji.

  Nuclear factor (NF) κB as a redox sensitive, anti-apoptotic and pro-inflammatory signaling molecule has been studied extensively for more than three decades. Its role in inducing antioxidant enzymes, defending against extracellular and intracellular stress and maintaining redox homeostasis in skeletal muscle has also been recognized. New research continues to explore the polytropic nature of NFκB in cellular function, especially its crosstalk with other important signaling pathways. Understanding of the broad impact of these functions has significant implications in health and disease of skeletal muscle as an organ designed for contraction and mobility. Two important aspects of muscle wellbeing, i.e., disease and aging, are not discussed in this review. This review will provide an update on the new findings related to NFκB involvement in multiple signaling pathways and refresh our knowledge of its activation in skeletal muscle with a special reference to physical exercise.

Keywords:  Nuclear Factor κ B; Pro-inflammatory cytokines; Reactive oxygen species; Redox signaling; Skeletal muscle

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.02.013
Skelet Muscle. 2025 Feb 24. 15(1): 4

ActRII or BMPR ligands inhibit skeletal myoblast differentiation, and BMPs promote heterotopic ossification in skeletal muscles in mice.

Marc A Egerman, Yuhong Zhang, Romain Donne, Jianing Xu, Abhilash Gadi, Corissa McEwen, Hunter Salmon, Kun Xiong, Yu Bai, Mary Germino, Kevin Barringer, Yasalp Jimenez, Maria Del Pilar Molina-Portela, Tea Shavlakadze, David J Glass.

   BACKGROUND: Prior studies suggested that canonical Activin Receptor II (ActRII) and BMP receptor (BMPR) ligands can have opposing, distinct effects on skeletal muscle depending in part on differential downstream SMAD activation. It was therefore of interest to test ActRII ligands versus BMP ligands in settings of muscle differentiation and in vivo.
METHODS AND RESULTS: In human skeletal muscle cells, both ActRII ligands and BMP ligands inhibited myogenic differentiation: ActRII ligands in a SMAD2/3-dependent manner, and BMP ligands via SMAD1/5. Surprisingly, a neutralizing ActRIIA/B antibody mitigated the negative effects of both classes of ligands, indicating that some BMPs act at least partially through the ActRII receptors in skeletal muscle. Gene expression analysis showed that both ActRII and BMP ligands repress muscle differentiation genes in human myoblasts and myotubes. In mice, hepatic BMP9 over-expression induced liver toxicity, caused multi-organ wasting, and promoted a pro-atrophy gene signature despite elevated SMAD1/5 signaling in skeletal muscle. Local overexpression of BMP7 or BMP9, achieved by intramuscular AAV delivery, induced heterotopic ossification. Elevated SMAD1/5 signaling with increased expression of BMP target genes was also observed in sarcopenic muscles of old rats.
CONCLUSIONS: The canonical ActRII ligand-SMAD2/3 and BMP ligand-SMAD1/5 axes can both block human myoblast differentiation. Our observations further demonstrate the osteoinductive function of BMP ligands while pointing to a potential relevancy of blocking the BMP-SMAD1/5 axis in the setting of therapeutic anti-ActRIIA/B inhibition.

Keywords:  ActRIIA/B; Activin A; BMP; BMPR2; GDF11; GDF8; Heterotopic ossification; Muscle differentiation; Myostatin; Skeletal muscle

DOI:  https://doi.org/10.1186/s13395-025-00373-7
PLoS One. 2025 ;20(2): e0318782

Transcriptomic adaptation of skeletal muscle in response to MICT and HIIT exercise modalities.

Weihao Hong, Yisheng Luan, Jianrong Zheng, Yingzhe Xiong, Bing Zhang, Yixuan Ma.

Skeletal muscle exhibits remarkable plasticity in response to diverse stimuli, with exercise serving as a potent trigger. Varied exercise modalities, including moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT), induce distinct structural and functional adaptations on skeletal muscle. However, the underlying molecular mechanisms governing these adaptations remain poorly understood. In this study, we utilized RNA-seq to characterize the transcriptomic profile of murine gastrocnemius muscle following 8-week treadmill-based MICT (M group) and HIIT (H group). A total of 1052 DEGs were screened in H vs. M. Among the top 10 significant DEGs, Foxo1 and Myod1 are closely related to muscular physiology. Through KEGG pathway analysis, distinct adaptations were primarily identified in the FoxO, MAPK, and PI3K-AKT pathways. By analyzing the expression of myokines, a significantly higher Igf-1 expression level was observed in the M group compared to the H group. Therefore, IGF-1, a well-known upstream regulator of both the PI3K-AKT-FoxO and MAPK pathways, might drive distinct muscle adaptations through variations in Igf-1 expression induced by these two exercise modalities.

DOI: https://doi.org/10.1371/journal.pone.0318782
FEBS J. 2025 Feb 22.

Stress exposure in the mdx mouse model of Duchenne muscular dystrophy provokes a widespread metabolic response.

Erynn E Johnson, James M Ervasti.

  Duchenne muscular dystrophy is a severe neuromuscular wasting disease that is caused by a primary defect in dystrophin protein and involves organism-wide comorbidities such as cardiomyopathy, metabolic and mitochondrial dysfunction, and nonprogressive cognitive impairments. Physiological stress exposure in the mdx mouse model of Duchenne muscular dystrophy results in phenotypic abnormalities that include locomotor inactivity, hypotension, and increased morbidity. Severe and lethal stress susceptibility in mdx mice corresponds to metabolic dysfunction in several coordinated metabolic pathways within dystrophin-deficient skeletal muscle, as well as prolonged elevation in mdx plasma corticosterone levels that extends beyond the wild-type (WT) stress response. Here, we performed a targeted mass spectrometry-based plasma metabolomics screen focused on biological stress pathways in healthy and dystrophin-deficient mdx mice exposed to mild scruff stress. One-third of the stress-relevant metabolites interrogated displayed significant elevation or depletion in mdx plasma after scruff stress and were restored to WT levels by skeletal muscle-specific dystrophin expression. The metabolic pathways of mdx mice altered by scruff stress are associated with regulation of the hypothalamic-pituitary-adrenal axis, locomotor tone, neurocognitive function, redox metabolism, cellular bioenergetics, and protein catabolism. Our data suggest that a mild stress triggers an exaggerated, multi-system metabolic response in mdx mice.

Keywords:  Duchenne muscular dystrophy; biological stress; metabolism; metabolomics; skeletal muscle

DOI:  https://doi.org/10.1111/febs.70029
PLoS One. 2025 ;20(2): e0318754

Soluble RAGE enhances muscle regeneration after cryoinjury in aged and diseased mice.

Naftali Horwitz, Michael Florea, K C Medha, Tina Liu, Vivian Garcia, Rebekah Kim, Amy Lam, Kathleen Messemer, Christopher Rios, Albert E Almada, Amy J Wagers.

The Receptor for Advanced Glycation End Products (RAGE), classically considered a mediator of acute and chronic inflammatory responses, has recently been implicated by genetic knockout studies as a regulator of skeletal muscle physiology during development and following acute injury. Yet, the role of its soluble isoform, soluble RAGE (sRAGE), in muscle regeneration remains relatively unexplored. To address this knowledge gap, Adeno-Associated Virus (AAV) mediated and genetic knockin supplementation strategies were developed to specifically assess the effects of changing levels of sRAGE on muscle regeneration. We evaluated general muscle physiology and histology, including central nucleation, and myofiber size. We found that acute induction of sRAGE in aged and atherosclerotic animals accelerates muscle repair after cryoinjury. Similarly, genetic modification of the endogenous Ager gene locus to favor production of sRAGE over transmembrane RAGE accelerates repair of cryo-damaged skeletal muscle. However, increasing sRAGE via AAV delivery or using our transgenic mouse lines had no impact on muscle repair in aged or diseased mice after barium chloride (BaCl2) injury. Together, these studies identify a unique muscle regulatory activity of sRAGE that is variable across injury models and may be targeted in a context-specific manner to alter the skeletal muscle microenvironment and boost muscle regenerative output.

DOI: https://doi.org/10.1371/journal.pone.0318754
J Physiol Sci. 2025 Feb 18. pii: S1880-6546(25)00008-3. [Epub ahead of print]75(1): 100012

Rebastinib inhibits FoxO1 activity and reduces dexamethasone-induced atrophy and its-related gene expression in cultured myotubes.

Tomoki Sato, Akihito Morita, Yui Watanabe, Yumi Naito, Haruka Kawaji, Takumi Nakagawa, Hiroki Hamaguchi, Yasuko Manabe, Nobuharu L Fujii, Naohisa Ogo, Akira Asai, Yasutomi Kamei, Shinji Miura.

  FoxO1, a transcription factor, is upregulated in skeletal muscle during atrophy and inactivation of FoxO1 is a potential strategy to prevent muscle loss. This study identified Rebastinib as a potent suppressor of FoxO1 activity among protein kinase inhibitors. To determine whether Rebastinib inhibits atrophy-related ubiquitin ligases gene expression and mitigates atrophy in mouse skeletal muscle-derived cells, we investigated its protective effects of the compound against dexamethasone (DEX)-induced muscle atrophy using C2C12 myotubes. Rebastinib inhibited the DEX-induced upregulation of atrogin-1 and MuRF-1 mRNA, and atrogin-1 protein. Rebastinib also suppressed protein degradation and increased myotube diameter in DEX-treated C2C12 myotubes. Additionally, Rebastinib ameliorated the DEX- and cachexia-induced reduction in contractile force generation. Although the precise mechanisms underlying the action of Rebastinib against muscle atrophy and its efficacy in vivo remains to be elucidated, this compound shows great potential as a therapeutic agent for muscle atrophy.

Keywords:  Cancer cachexia; Dexamethasone; FoxO1 inhibition; Muscle atrophy; Rebastinib

DOI:  https://doi.org/10.1016/j.jphyss.2025.100012
Sci Adv. 2024 Oct 11. 10(41): eadq6795

CLIC5 promotes myoblast differentiation and skeletal muscle regeneration via the BGN-mediated canonical Wnt/β-catenin signaling pathway.

Xin Zhang, Linjuan He, Liqi Wang, Yubo Wang, Enfa Yan, Boyang Wan, Qiuyu Zeng, Pengguang Zhang, Xingbo Zhao, Jingdong Yin.

Myoblast differentiation plays a vital role in skeletal muscle regeneration. However, the protein-coding genes controlling this process remain incompletely understood. Here, we showed that chloride intracellular channel 5 (CLIC5) exerts a critical role in mediating myogenesis and skeletal muscle regeneration. Deletion of CLIC5 in skeletal muscle leads to reduced muscle weight and decreases the number and differentiation potential of satellite cells. In vitro, CLIC5 consistently inhibits myoblast proliferation while promoting myotube formation. CLIC5 promotes myogenic differentiation by activating the canonical Wnt/β-catenin signaling pathway in a biglycan (BGN)-dependent manner. CLIC5 deletion impairs muscle regeneration. Paired box gene 7 (Pax7) expression and the activity of BGN-mediated canonical Wnt/β-catenin signaling are reduced in CLIC5-deficient mice. Conversely, increasing CLIC5 levels in skeletal muscles enhances muscle regeneration capacity. In conclusion, our findings underscore CLIC5 as a pivotal regulator of myogenesis and skeletal muscle regeneration, functioning through interaction with BGN to activate the canonical Wnt/β-catenin signaling pathway.

DOI: https://doi.org/10.1126/sciadv.adq6795
Genes (Basel). 2025 Jan 26. pii: 153. [Epub ahead of print]16(2):

Effects of Physical Exercise on MuRF-1/TRIM63 mRNA Expression in Humans: A Systematic Review.

Leonardo Henrique Silva Fagundes, Eduardo Mendonça Pimenta, Varley Teoldo da Costa.

   BACKGROUND/OBJECTIVES: Muscle-specific RING finger protein 1 (MuRF-1) is a pivotal regulator of muscle protein breakdown, an essential process for post-exercise muscle adaptation. This systematic review aimed to evaluate the effects of physical exercise on MuRF-1 mRNA expression in humans.
METHODS: A literature search was conducted in PubMed, Scopus, Cochrane Library, Google Scholar, and Web of Science following the PRISMA guidelines. The search was limited to studies published from 1 January 2001 to 1 December 2024. The inclusion and exclusion criteria were defined using the PICOS strategy. Two investigators independently performed the study selection, data extraction, and assessment of methodological quality, with any disagreements resolved by a third investigator. The PEDro scale was used to evaluate the risk of bias.
RESULTS: Forty-six studies met the eligibility criteria and were included. The findings evidenced that physical exercise significantly modulates MuRF-1 mRNA expression in humans. Resistance exercise induces transient increases, typically peaking between 1 and 4 h, whereas endurance exercise elicits similar responses within 40 min to 4 h post-exercise. Combined exercise protocols that include resistance and endurance exercises significantly increased MuRF-1 mRNA expression at 3 h post-exercise. The effects of physical exercise on MuRF-1 mRNA expression are influenced by factors such as exercise order, intensity, contraction mode, age, sex, and fitness level.
CONCLUSIONS: This systematic review shows that MuRF-1 mRNA expression is significantly modulated by physical exercise in humans and is sensitive to different exercise modalities. These findings suggest that this key protein involved in muscle protein breakdown and turnover is essential for exercise-induced adaptations, contributing to skeletal muscle recovery and remodeling after exercise.

Keywords:  MuRF-1/TRIM63; gene expression; human skeletal muscle signaling; muscle protein degradation; physical performance

DOI:  https://doi.org/10.3390/genes16020153
J Appl Physiol (1985). 2025 Feb 27.

Oral contraceptive pill phase does not influence muscle protein synthesis or myofibrillar proteolysis at rest or in response to resistance exercise.

Lauren M Colenso-Semple, James McKendry, Changhyun Lim, Philip J Atherton, Daniel J Wilkinson, K Smith, Stuart M Phillips.

  There is speculation that oral contraceptive pill (OCP) use affects skeletal muscle biology and protein turnover in response to resistance exercise; however, research in this area is scarce. We aimed to assess, using stable isotope tracers and skeletal muscle biopsies, how second-generation OCP phase affected muscle protein synthesis and whole-body proteolysis. Participants (n=12) completed two 6-day study phases in a randomized order: an active pill phase (Active; week two of a monthly active OCP cycle) and an inactive pill phase (Inactive; final week of a monthly OCP cycle). Participants performed unilateral resistance exercise in each study phase, exercising the contralateral leg in the opposite phase in a randomized, counterbalanced order. The Active phase myofibrillar protein synthesis (MPS) rates were 1.44 ± 0.14 %•d-1 in the control leg and 1.64 ± 0.15 %•d-1 in the exercise leg (p < 0.001). The Inactive phase MPS rates were 1.49 ± 0.12 %•d-1 %/d in the control leg and 1.71 ± 0.16 %•d-1 in the exercise leg (p < 0.001), with no interaction between phases (p = 0.63). There was no significant effect of OCP phase on whole-body myofibrillar proteolytic rate (active phase k = 0.018 ± 0.01; inactive phase k = 0.018 ± 0.006; p = 0.55). Skeletal muscle remains equally as responsive, in terms of stimulation of MPS, during Active and Inactive OCP phases; hence, our data does not support a pro-anabolic or catabolic, based on myofibrillar proteolysis, effect of OCP phase on skeletal muscle in females.

Keywords:  Anabolism; Female; Protein turnover; Resistance exercise

DOI:  https://doi.org/10.1152/japplphysiol.00035.2025
Cells. 2025 Feb 07. pii: 237. [Epub ahead of print]14(4):

NE-MTOC Formation in Skeletal Muscle Is Mbnl2-Dependent and Occurs in a Sequential and Gradual Manner.

Payel Das, Robert Becker, Silvia Vergarajauregui, Felix B Engel.

  Non-centrosomal microtubule-organizing centers (ncMTOCs) are important for the function of differentiated cells. Yet, ncMTOCs are poorly understood. Previously, several components of the nuclear envelope (NE)-MTOC have been identified. However, the temporal localization of MTOC proteins and Golgi to the NE and factors controlling the switch from a centrosomal MTOC to a ncMTOC remain elusive. Here, we utilized the in vitro differentiation of C2C12 mouse myoblasts as a model system to study NE-MTOC formation. We find based on longitudinal co-immunofluorescence staining analyses that MTOC proteins are recruited in a sequential and gradual manner to the NE. AKAP9 localizes with the Golgi to the NE after the recruitment of MTOC proteins. Moreover, siRNA-mediated depletion experiments revealed that Mbnl2 is required for proper NE-MTOC formation by regulating the expression levels of AKAP6β. Finally, Mbnl2 depletion affects Pcnt isoform expression. Taken together, our results shed light on how mammals post-transcriptionally control the switch from a centrosomal MTOC to an NE-MTOC and identify Mbnl2 as a novel modulator of ncMTOCs in skeletal muscle cells.

Keywords:  MTOC; Mbnl2; non-centrosomal microtubule-organizing center; nuclear envelope; pericentrin; skeletal muscle; splicing

DOI:  https://doi.org/10.3390/cells14040237
Life Med. 2024 Dec;3(6): lnaf001

A framework of biomarkers for skeletal muscle aging: a consensus statement by the Aging Biomarker Consortium.

Aging Biomarker Consortium

The skeletal muscle is an important organ for movement and metabolism in human body, and its physiological aging underlies the occurrence of muscle atrophy and sarcopenia. China has the largest aging population in the world and is facing a grand challenge with how to prevent and treat skeletal muscle aging-related diseases. To address this difficult problem, the Aging Biomarker Consortium (ABC) of China has reached an expert consensus on biomarkers of skeletal muscle aging by synthesizing literatures and insights from scientists and clinicians. This consensus attempts to provide a comprehensive assessment of biomarkers associated with skeletal muscle aging, and proposes a systematic framework to classify them into three dimensions: functional, structural, and humoral. Within each dimension, the experts recommend clinically relevant biomarkers for skeletal muscle aging. This consensus aims to lay the foundation for future research on skeletal muscle aging, facilitating precise prediction, diagnosis, and treatment of skeletal muscle aging and sarcopenia. It is anticipated to make significant contributions to healthy aging of skeletal muscle in the elderly population in China and around the world as well.

DOI: https://doi.org/10.1093/lifemedi/lnaf001
Nat Rev Endocrinol. 2025 Feb 26.

Bone and muscle crosstalk in ageing and disease.

Ben Kirk, Giovanni Lombardi, Gustavo Duque.

Interorgan communication between bone and skeletal muscle is central to human health. A dysregulation of bone-muscle crosstalk is implicated in several age-related diseases. Ageing-associated changes in endocrine, inflammatory, nutritional and biomechanical stimuli can influence the differentiation capacity, function and survival of mesenchymal stem cells and bone-forming and muscle-forming cells. Consequently, the secretome phenotype of bone and muscle cells is altered, leading to impaired crosstalk and, ultimately, catabolism of both tissues. Adipose tissue acts as a third player in the bone-muscle interaction by secreting factors that affect bone and muscle cells. Physical exercise remains the key biological stimulus for bone-muscle crosstalk, either directly via the release of cytokines from bone, muscle or adipocytes, or indirectly through extracellular vesicles. Overall, bone-muscle crosstalk is considered an inherent process necessary to maintain the structure and function of both tissues across the life cycle. This Review summarizes the latest biomedical advances in bone-muscle crosstalk as it pertains to human ageing and disease. We also outline future research priorities to accommodate the understanding of this rapidly emerging field.

DOI: https://doi.org/10.1038/s41574-025-01088-x
Cells. 2025 Feb 08. pii: 244. [Epub ahead of print]14(4):

Withaferin A Attenuates Muscle Cachexia Induced by Angiotensin II Through Regulating Pathways Activated by Angiotensin II.

Sham S Kakar, Vasa Vemuri, Mariusz Z Ratajczak.

  Cachexia is a multifactorial syndrome characterized by severe muscle wasting and is a debilitating condition frequently associated with cancer. Previous studies from our group revealed that withaferin A (WFA), a steroidal lactone, mitigated muscle cachexia induced by ovarian tumors in NSG mice. However, it remains unclear whether WFA's protective effects are direct or secondary to its antitumor properties. We developed a cachectic model through continuous angiotensin II (Ang II) infusion in C57BL/6 mice to address this issue. Ang II infusion resulted in profound muscle atrophy, evidenced by significant reductions in grip strength and in the TA, GA, and GF muscle mass. Molecular analyses indicated elevated expression of inflammatory cytokines (TNFα, IL-6, MIP-2, IL-18, IL-1β), NLRP3 inflammasome, and genes associated with the UPS (MuRF1, MAFBx) and autophagy pathways (Bacl1, LC3B), along with suppression of anti-inflammatory heme oxygenase-1 (HO-1) and myogenic regulators (Pax7, Myod1). Strikingly, WFA treatment reversed these pathological changes, restoring muscle mass, strength, and molecular markers to near-normal levels. These findings demonstrate that WFA exerts direct anti-cachectic effects by targeting key inflammatory and atrophic pathways in skeletal muscle, highlighting its potential as a novel therapeutic agent for cachexia management.

Keywords:  Ang II; cytokines; muscle cachexia; muscle function; withaferin A

DOI:  https://doi.org/10.3390/cells14040244
Biomedicines. 2025 Feb 14. pii: 474. [Epub ahead of print]13(2):

ADAMTS4 Reduction Contributes to Extracellular Matrix Deposition and Impaired Myogenesis in the Skeletal Muscle of Cigarette Smoke-Exposed Mice.

Danyang Li, Yuqiang Pei, Long Liang, Zihan Wang, Xiaoyan Gai, Yongchang Sun.

  Background: The extracellular matrix (ECM) plays a critical role in the proper regeneration of skeletal muscle. ECM remodeling has been reported in the skeletal muscle of chronic obstructive pulmonary disease (COPD), while the mechanisms remain poorly understood. Methods: In this study, we examined the dynamic interplay between ECM components and ECM enzymes in COPD skeletal muscle and cigarette smoke (CS) extract-treated C2C12 cells. C2C12 cells were further used to evaluate the role of a disintegrin and metalloproteinase with thrombospondin motif 4 (ADAMTS4) in ECM remodeling and myogenesis. Results: Chronic CS exposure induced the development of COPD and comorbid sarcopenia in C57BL/6J mice. Muscle fibrosis was observed in the gastrocnemius muscle of CS-exposed mice, accompanied by an upregulation of protein expression but a downregulation of mRNA levels of fibronectin and versican. We found that the discrepancy of mRNA and protein expression was attributed to the aberrant secretion of some ECM enzymes belonging to matrix metalloproteinases and ADAMTS proteases, especially ADAMTS4. CS exposure reduced ADAMTS4 expression in gastrocnemius muscles and C2C12 cells, and Adamts4 knockdown induced fibronectin and versican accumulation and impeded myogenic process. Conclusions: Considering that recent studies have indicated an impaired skeletal muscle regeneration in COPD, we suggested that the restrained production of ADAMTS4 in response to CS could be involved in the damaged muscle regeneration through regulating skeletal muscle ECM in COPD. Targeting ECM enzymes may benefit the rehabilitation of COPD-related sarcopenia.

Keywords:  ADAMTS4; COPD; chronic obstructive pulmonary disease; cigarette smoke; extracellular matrix

DOI:  https://doi.org/10.3390/biomedicines13020474
J Inflamm Res. 2025 ;18 2447-2464

Cigarette Smoking Induces Skeletal Muscle Atrophy in Mice by Activated Macrophage-Mediated Pyroptosis.

Yufen Tan, Yuanyuan Ye, Cuibi Huang, Jie Li, Lihua Huang, Xinyan Wei, Tong Liang, Enyuan Qin, Guolin Xiong, Yanfei Bin.

   Objective: Skeletal muscle atrophy is a major comorbidity associated with chronic obstructive pulmonary disease caused by exposure to cigarette smoke (CS). CS-activated macrophages and pyroptosis play an important role in skeletal muscle atrophy, but its specific molecular mechanism remains unclear. This study investigated the role and mechanisms of pyroptosis and activated macrophages in CS-induced skeletal muscle atrophy.
Methods: In the in vivo model, mice were exposed to either CS or air for 24 weeks, and in the in vitro model, C2C12 murine skeletal muscle cells were co-cultured with macrophages in Transwell chambers. Western blotting, real-time PCR, ELISA, and other methods were used to detect pyroptosis-related markers to investigate the mechanism of CSE-activated macrophages on skeletal muscle atrophy and pyroptosis.
Results: In vivo, CS-induced atrophy of the mouse gastrocnemius muscle was accompanied by increased expression of pyroptosis-related markers, including NLRP3 inflammasome, cleaved Caspase-1, the GSDMD N-terminal domain, and interleukin (IL)-18. In vitro, CS extract (CSE)-activated macrophages mediates pyroptosis of skeletal muscle cells and induces myotube atrophy. Further studies demonstrated that macrophage-derived TNF-α is the initiating factor of skeletal muscle pyroptosis, and this process appears to be mediated through TNF-α activating the TNFR1/NLRP3/caspase-1/GSDMD signaling pathway.
Conclusion: TNF-α released by CSE-activated macrophages can promote skeletal muscle pyroptosis by activating the TNFR1/NLRP3/Caspase-1/GSDMD signaling pathway, which likely contributes to skeletal muscle atrophy. These findings provide more insight into the mechanisms underlying skeletal muscle atrophy in COPD.

Keywords:  chronic obstructive pulmonary disease; cigarette smoke; macrophages; pyroptosis; skeletal muscle atrophy

DOI:  https://doi.org/10.2147/JIR.S497631
J Physiol. 2025 Feb 26.

Dietary nitrate supplementation mitigates age-related changes at the neuromuscular junction in mice.

Maira Rossi, Lucrezia Zuccarelli, Lorenza Brocca, Cristiana Sazzi, Clarissa Gissi, Paola Rossi, Bruno Grassi, Simone Porcelli, Roberto Bottinelli, Maria Antonietta Pellegrino.

  In ageing, denervation and neuromuscular junction (NMJ) instability occur alongside mitochondrial alterations and redox unbalance, potentially playing a significant role in the process. Moreover, the synthetic pathway was shown to be critical for proper innervation and NMJ stability. Nitric oxide (NO) modulates redox status, mitochondrial function and the synthetic pathway. Its bioavailability declines with age. We hypothesize that nitrate supplementation could counteract age-related neuromuscular alterations. We compared young (Y) (7 months old), old (O) (24 months old) and old mice supplemented daily with 1.5 mm inorganic NaNO3 dissolved in drinking water for 8 weeks (ON) (24 months old). Compared to Y, O mice displayed impaired NO signalling and transport (lower phosphorylated-neuronal NO synthase and sialin content); greater nitrosative and oxidative stress (higher 3-nitrotyrosine levels and protein carbonylation); lower glutathione peroxidase (GPX antioxidant enzyme); smaller muscle fibres; and larger muscle fibrosis. NMJ integrity was impaired, exhibiting age-related alterations such as larger fragmentation, lower overlap, larger endplate areas and lower compactness. Consistently, greater expression of denervation-associated markers (Gadd45α, MyoG, RUNX1, AChRγ and NCAM1) and higher NCAM1+ fibres percentage suggested denervation. Importantly, mitochondrial content, dynamics and function were unchanged. Compared to O, ON mice showed improved NO bioavailability in muscle (higher nitrate-nitrite concentration); lower fibrosis and improved muscle fibre size; higher phosphorylation of P70S6K and S6, downstream factors of Akt/mammalian target of rapamycin synthetic pathway; lower oxidative stress (lower carbonylated proteins and mitochondrial hydrogen peroxide production, higher GPX protein levels); reverted age-related alterations of NMJ morphology; and lower percentage of NCAM1+ fibres. Nitrate supplementation could be a therapeutic strategy to counteract muscle decline with ageing. KEY POINTS: Ageing leads to instability at the neuromuscular junction (NMJ), which is crucial for muscle size and function, ultimately giving rise to denervation and muscle fibres loss. Mitochondrial function, redox status and activation of synthetic pathway are critical processes for proper muscle innervation and stability of the NMJ. Nitric oxide was shown to modulate intracellular processes involved in NMJ stability such as balance of reactive oxygen species, mitochondrial function and protein synthesis. Its bioavailability decreases with ageing. Our study shows that nitrate supplementation in old mice improved redox balance, enhanced the anabolic pathway and stabilized nerve-muscle interactions, suggesting a potential strategy to mitigate the neuromuscular decline associated with ageing.

Keywords:  ageing; extensor digitorum longus; gastrocnemius; mitochondria; neuromuscular junction; nitrate supplementation; oxidative stress; tibialis anterior

DOI:  https://doi.org/10.1113/JP287592
J Cachexia Sarcopenia Muscle. 2025 Apr;16(2): e13738

Low-Carbohydrate Diet Exacerbates Denervation-Induced Atrophy of Rat Skeletal Muscle Under the Condition of Identical Protein Intake.

Aki Yokogawa, Kohei Kido, Ikuru Miura, Eisuke Oyama, Daisuke Takakura, Keigo Tanaka, Daniel J Wilkinson, Kenneth Smith, Philip J Atherton, Kentaro Kawanaka.

   BACKGROUND: While decreased protein intake is associated with muscle mass loss, it is unclear whether a decrease in carbohydrate intake adversely affects muscle atrophy independently of protein intake. Herein, we examined whether a low-carbohydrate (low-CHO) diet exacerbates denervation-induced muscle atrophy under conditions of identical protein intake.
METHODS: On day one of the experiment, male Wistar rats underwent unilateral denervation. The contralateral leg was used as the control. After denervation, rats were divided into two dietary groups: high-carbohydrate (high-CHO) and low-CHO. Each group was fed a high-CHO (70% carbohydrate) or low-CHO (20% carbohydrate) diet over 7 days. Total protein and energy intakes in both groups were matched by pair feeding. Rats were provided with deuterium oxide (D2O) tracer over the last 3 days of dietary intervention to quantify myofibrillar (muscle) protein synthesis (MPS).
RESULTS: Denervation reduced wet weight of the gastrocnemius muscle compared to the contralateral control (p < 0.05). Reductions in gastrocnemius muscle weight were greater in the low-CHO group (-34%) than the high-CHO group (-28%) (p < 0.05). Although denervation decreased MPS compared to the contralateral control (p < 0.05), no dietary effect on MPS was observed. Denervation resulted in increased mRNA and protein expression of Atrogin-1, a ubiquitin E3 ligase, compared to that in the contralateral control (p < 0.05). Increases in Atrogin-1 gene and protein expression due to denervation were greater in the low-CHO group than in the high-CHO group (p < 0.05).
CONCLUSIONS: We conclude that a low-CHO diet may exacerbate denervation-induced atrophy in fast-twitch-dominant muscles compared to a high-CHO diet, even when the same protein intake is maintained. Although blunted MPS contributed to muscle atrophy due to denervation, exacerbation of muscle atrophy by the low-CHO diet was not accompanied by explanatory changes in MPS. The effect of the low-CHO diet might be related to promotion of muscle-specific ubiquitin E3 ligase gene expression.

Keywords:  AMPK; Atrogin‐1; deuterium oxide; low‐carbohydrate diet; myofibrillar protein synthesis rate

DOI:  https://doi.org/10.1002/jcsm.13738
Int J Mol Sci. 2025 Feb 12. pii: 1539. [Epub ahead of print]26(4):

Human iPSC-Derived Muscle Cells as a New Model for Investigation of EDMD1 Pathogenesis.

Marta Lisowska, Marta Rowińska, Aleksandra Suszyńska, Claudia Bearzi, Izabela Łaczmańska, Julia Hanusek, Amanda Kunik, Volha Dzianisava, Ryszard Rzepecki, Magdalena Machowska, Katarzyna Piekarowicz.

  Emery-Dreifuss muscular dystrophy type 1 (EDMD1) is a rare genetic disease caused by mutations in the EMD gene, which encodes the nuclear envelope protein emerin. Despite understanding the genetic basis of the disease, the molecular mechanism underlying muscle and cardiac pathogenesis remains elusive. Progress is restricted by the limited availability of patient-derived samples; therefore, there is an urgent need for human-specific cellular models. In this study, we present the generation and characterization of induced pluripotent stem cell (iPSC) lines derived from EDMD1 patients carrying EMD mutations that lead to truncated or absent emerin, together with iPSCs from healthy donor. The patient-specific iPSCs exhibit stable karyotypes, maintain appropriate morphology, express pluripotency markers, and demonstrate the ability to differentiate into three germ layers. To model EDMD1, these iPSCs were differentiated into myogenic progenitors, myoblasts, and multinucleated myotubes, which represent all stages of myogenesis. Each developmental stage was validated by the presence of stage-specific markers, ensuring the accuracy of the model. We present the first iPSC-based in vitro platform that captures the complexity of EDMD1 pathogenesis during myogenesis. This model can significantly contribute to understanding disease mechanisms and develop the targeted therapeutic strategies for EDMD1.

Keywords:  EMD mutation; Emery–Dreifuss muscular dystrophy; disease modeling; emerin; muscle differentiation in vitro; skeletal muscles; stem cells

DOI:  https://doi.org/10.3390/ijms26041539
Am J Physiol Cell Physiol. 2025 Feb 28.

Optimizing Electrical Field Stimulation Parameters Reveals the Maximum Contractile Function of Human Skeletal Muscle Microtissues.

Yekaterina Tiper, Zhuoye Xie, Arne Daniel Hofemeier, Heta Lad, Mattias Luber, Roman Krawetz, Timo Betz, Wolfram-Hubertus Zimmermann, Aaron B Morton, Steven S Segal, Penney M Gilbert.

  Skeletal muscle microtissues are engineered to develop therapies for restoring muscle function in patients. However, optimal electrical field stimulation (EFS) parameters to evaluate the function of muscle microtissues remain unestablished. This study reports a protocol to optimize EFS parameters for eliciting contractile force of muscle microtissues cultured in micropost platforms. Muscle microtissues were produced across an opposing pair of microposts in polydimethylsiloxane and polymethyl methacrylate culture platforms using primary, immortalized, and induced pluripotent stem cell-derived myoblasts. In response to EFS between needle electrodes, contraction deflects microposts proportional to developed force. At 5 V, pulse durations used for native muscle (0.1-1 ms) failed to elicit contraction of microtissues; durations reported for engineered muscle (5-10 ms) failed to elicit peak force. Instead, pulse durations of 20-80 ms were required to elicit peak twitch force across microtissues derived from 5 myoblast lines. Similarly, while peak tetanic force occurs at 20-50 Hz for native human muscles, it varied across microtissues depending on the cell line type, ranging from 7-60 Hz. A new parameter, the dynamic oscillation of force, captured trends during rhythmic contractions, while quantifying the duration-at-peak force provides an extended kinetics parameter. Our findings indicate that muscle microtissues have cell line type-specific contractile properties, yet all contract and relax more slowly than native muscle, implicating underdeveloped excitation-contraction coupling. Failure to optimize EFS parameters can mask the functional potential of muscle microtissues by underestimating force production. Optimizing and reporting EFS parameters and metrics is necessary to leverage muscle microtissues for advancing skeletal muscle therapies.

Keywords:  contractile function; electrical field stimulation; engineered skeletal muscle; induced pluripotent stem cells; micropost platform

DOI:  https://doi.org/10.1152/ajpcell.00308.2024
Biomolecules. 2025 Feb 11. pii: 261. [Epub ahead of print]15(2):

Evolutionary Insights into Irisin/FNDC5: Roles in Aging and Disease from Drosophila to Mammals.

Kiwon Lee, Myungjin Kim.

  The Irisin/FNDC5 protein family has emerged as a pivotal link between exercise and the prevention of age-associated diseases. Irisin is highly expressed during exercise from skeletal and cardiac muscle cells, playing a critical role in mediating systemic health benefits through its actions on various tissues. However, Irisin levels decline with age, correlating with a heightened incidence of diseases such as muscle weakness, cardiovascular disorders, and neurodegeneration. Notably, the administration of Irisin has shown significant potential in both preventing and treating these conditions. Recently, an Irisin/FNDC5 homolog was identified in an invertebrate Drosophila model, providing valuable insights into its conserved role in exercise physiology. Importantly, Irisin/FNDC5 has been demonstrated to regulate autophagy-a process essential for clearing excessive nutrients, toxic aggregates, and dysfunctional organelles-in both flies and mammals. Dysregulated autophagy is often implicated in age-related diseases, highlighting its relevance to Irisin/FNDC5's functions. These findings deepen our understanding of Irisin/FNDC5's roles and its potential as a therapeutic target for mitigating aging-related health decline. Further studies are needed to elucidate the precise mechanisms by which Irisin regulates autophagy and its broader impact on physiological aging and related diseases.

Keywords:  Drosophila; FNDC5; Iditarod; Irisin; aging; exercise

DOI:  https://doi.org/10.3390/biom15020261
bioRxiv. 2025 Feb 11. pii: 2025.02.10.635159. [Epub ahead of print]

GL261 glioblastoma induces delayed body weight gain and stunted skeletal muscle growth in young mice.

Joshua R Huot, Nicholas A Jamnick, Fabrizio Pin, Patrick D Livingston, Chandler S Callaway, Andrea Bonetto.

Introduction: The survival rate for children and adolescents has increased to over 85%. However, there is limited understanding of the impact of pediatric cancers on muscle development and physiology. Given that brain tumors alone account for 26% of all pediatric cancers, this study aimed to investigate the skeletal muscle consequences of tumor growth in young mice.
Methods: C2C12 myotubes were co-cultured with GL261 murine glioblastoma cells to assess myotube size. GL261 cells were then injected subcutaneously into 4-week-old male C57BL/6J mice. Animals were euthanized 28 days post-GL261 implantation. Muscle function was tested in vivo and ex vivo . Muscle protein synthesis was measured via the SUnSET method, and gene/protein expression levels were assessed via Western blotting and qPCR.
Results: In vitro , the C2C12 cultures exposed to GL261 exhibited myotube atrophy, consistent with a disrupted anabolic/catabolic balance. In vivo , carcass, heart, and fat mass were significantly reduced in the tumor-bearing mice. Skeletal muscle growth was impeded in the GL261 hosts, along with smaller muscle CSA. Both in vivo muscle torque and the ex vivo EDL muscle force were unchanged. At molecular level, the tumor hosts displayed reduced muscle protein synthesis and increased muscle protein ubiquitination, in disagreement with decreased muscle ubiquitin ligase mRNA expression.
Conclusions: Overall, we showed that GL261 tumors impact the growth of pediatric mice by stunting skeletal muscle development, decreasing muscle mass, reducing muscle fiber size, diminishing muscle protein synthesis, and altering protein catabolism signaling.

DOI: https://doi.org/10.1101/2025.02.10.635159
Life Sci. 2025 Feb 24. pii: S0024-3205(25)00141-9. [Epub ahead of print] 123507

Aging-related hyperphosphatemia triggers the release of TNF-α from macrophages, promoting indicators of sarcopenia through the reduction of IL-15 expression in skeletal muscle.

Elena Alcalde-Estévez, Ariadna Moreno-Piedra, Ana Asenjo-Bueno, María Martos-Elvira, Mariano de la Serna-Soto, Marta Ruiz-Ortega, Gemma Olmos, Susana López-Ongil, María P Ruiz-Torres.

   AIMS: The association between aging-related hyperphosphatemia and sarcopenia has been documented, and evidence suggests that inflammaging is involved in the manifestation of sarcopenia. The present study investigates whether hyperphosphatemia triggers inflammation, thereby inducing the appearance of sarcopenia along with the cytokines involved in these processes.
MATERIALS AND METHODS: RAW 264.7 macrophages were incubated with β-glycerophosphate (BGP), as a phosphate donor, at different time intervals, to assess the production of proinflammatory markers. Conditioned medium from macrophages was collected and added to cultured C2C12 myoblasts to analyse whether proinflammatory molecules, released by macrophages, modified myogenic differentiation, cell senescence or myokine IL-15 expression. A neutralising antibody anti-TNF-α and recombinant IL-15 were added to evaluate the role of these cytokines in the observed effects. Additionally, TNF-α, IL-15, serum phosphate, and sarcopenia signs were evaluated in 5-month-old mice, 24-month-old mice and 24-month-old mice fed with a hypophosphatemic diet.
KEY FINDINGS: BGP increased TNF-α expression in macrophages through NFkB activation. Conditioned medium from BGP-treated macrophages impaired myogenic differentiation in differentiating myoblasts and promoted cellular senescence and reduced IL-15 expression in undifferentiated myoblasts. These effects were mediated by TNF-α. Old mice displayed reduced expression of muscle IL-15 and elevated circulating TNF-α, along with increased serum phosphate levels, which correlated with the appearance of sarcopenia indicators. The hypophosphatemic diet prevented these changes in old mice.
SIGNIFICANCE: Hyperphosphatemia induces TNF-α production in macrophages, which contributes to the reduced expression of muscular IL-15. This mechanism may play a role in inducing sarcopenia in elderly mice.

Keywords:  Cellular senescence; Hyperphosphatemia; IL-15; Inflammaging; Myoblasts differentiation; Sarcopenia

DOI:  https://doi.org/10.1016/j.lfs.2025.123507
Nat Commun. 2025 Feb 24. 16(1): 1936

Structural insights into transmembrane helix S0 facilitated RyR1 channel gating by Ca2+/ATP.

Risheng Wei, Qiang Chen, Lei Zhang, Congcong Liu, Chuang Liu, Chang-Cheng Yin, Hongli Hu.

The type-1 ryanodine receptor (RyR1) is an intracellular calcium release channel for skeletal muscle excitation-contraction coupling. Previous structural studies showed that the RyR1 activity is modulated by the exogenous regulators including caffeine, ryanodine, PCB-95 and diamide. An additional transmembrane helix, located adjacent to S1 and S4, has been observed in some structures, although its function remains unclear. Here, we report that using a mild purification procedure, this helix is co-purified with RyR1 and is designated as S0. When RyR1 is coupled with S0, it can be activated by Ca2+ to an open state; however when decoupled from S0, it remains in primed state. S0 regulates the channel conformation by directly affecting the TM domain via the pVSD-S0-S4/S5 linker coupling, which facilitates the dilation of S6. Our results demonstrate that S0 is an essential component of RyR1 and plays a key role in the physiological regulation of RyR1 channel gating.

DOI: https://doi.org/10.1038/s41467-025-57074-4
Autophagy Rep. 2024 ;pii: 2434379. [Epub ahead of print]3(1):

Alterations of PINK1-PRKN signaling in mice during normal aging.

Zahra Baninameh, Jens O Watzlawik, Xu Hou, Tyrique Richardson, Nicholas W Kurchaba, Tingxiang Yan, Damian N Di Florio, DeLisa Fairweather, Lu Kang, Justin H Nguyen, Takahisa Kanekiyo, Dennis W Dickson, Sachiko Noda, Shigeto Sato, Nobutaka Hattori, Matthew S Goldberg, Ian G Ganley, Kelly L Stauch, Fabienne C Fiesel, Wolfdieter Springer.

  The ubiquitin kinase-ligase pair PINK1-PRKN identifies and selectively marks damaged mitochondria for elimination via the autophagy-lysosome system (mitophagy). While this cytoprotective pathway has been extensively studied in vitro upon acute and complete depolarization of mitochondria, the significance of PINK1-PRKN mitophagy in vivo is less well established. Here we used a novel approach to study PINK1-PRKN signaling in different energetically demanding tissues of mice during normal aging. We demonstrate a generally increased expression of both genes and enhanced enzymatic activity with aging across tissue types. Collectively our data suggest a distinct regulation of PINK1-PRKN signaling under basal conditions with the most pronounced activation and flux of the pathway in mouse heart compared to brain or skeletal muscle. Our biochemical analyses complement existing mitophagy reporter readouts and provide an important baseline assessment in vivo, setting the stage for further investigations of the PINK1-PRKN pathway during stress and in relevant disease conditions.

Keywords:  PINK1; PRKN; aging; brain; heart; mice; mitochondria; mitophagy; phosphorylated ubiquitin; skeletal muscle

DOI:  https://doi.org/10.1080/27694127.2024.2434379
Cell Metab. 2025 Feb 14. pii: S1550-4131(25)00025-7. [Epub ahead of print]

Leptin enhances the intracellular thyroid hormone activation in skeletal muscle to boost energy balance.

Caterina Miro, Annunziata Gaetana Cicatiello, Annarita Nappi, Serena Sagliocchi, Lucia Acampora, Federica Restolfer, Ornella Cuomo, Giulia de Alteris, Gabriella Pugliese, Sepehr Torabinejad, Rosa Maritato, Melania Murolo, Emery Di Cicco, Nunzio Velotti, Marianna Capuano, Evelina La Civita, Daniela Terracciano, Roberto Ciampaglia, Mariano Stornaiuolo, Mario Musella, Giovanni Aprea, Giuseppe Pignataro, Silvia Savastano, Monica Dentice.

  Thyroid hormones (THs) are key modulators of energy metabolism and cross-talk with other endocrine and metabolic factors. Notably, leptin can increase hypothalamic control of TH synthesis as an adaptive metabolic response regulating body weight. In this study, we found that the TH signal is heightened in overweight humans and is lost with obesity. In mice, systemic and intracerebroventricular leptin injection induces the expression of type 2 deiodinase (D2), the TH-activating enzyme, in skeletal muscle. Mechanistically, leptin enhances the transcription of D2 by a STAT3- and α-melanocyte-stimulating hormone (α-MSH)/cyclic AMP (cAMP)-dependent regulation. Notably, mice lacking D2 or with a mutation in the TH receptor do not exhibit the metabolic effects of leptin, such as increased insulin sensitivity and oxygen consumption, indicating that leptin's peripheral metabolic effects in skeletal muscle are mediated by TH. These findings underscore the critical role of leptin in integrating the TH-induced metabolic activation, while also contributing to appetite suppression in response to perceived fat stores.

Keywords:  deiodinases; energy homeostasis; glucose uptake; leptin; melanocortin; obesity; skeletal muscle; thyroid hormone

DOI:  https://doi.org/10.1016/j.cmet.2025.01.025
Physiol Genomics. 2025 Feb 27.

Divergent Multiomic Acute Exercise Responses Reveal the Impact of Sex as a Biological Variable.

Kaleen M Lavin, Samia M O'Bryan, Khyatiben V Pathak, Krystine Garcia-Mansfield, Zachary A Graham, Jeremy S McAdam, Devin J Drummer, Margaret B Bell, Christian J Kelley, Manoel E Lixandrão, Brandon Peoples, Regina S Seay, Anakaren R Torres, Rebecca Reiman, Eric Alsop, Elizabeth Hutchins, Anna Bonfitto, Jerry Antone, Joanna Palade, Kendall Van Keuren-Jensen, Matthew J Huentelman, Patrick Pirrotte, Timothy Broderick, Marcas M Bamman.

  The majority of exercise physiology research has been conducted in males, resulting in a skewed biological representation of how exercise impacts the physiological system. Extrapolating male-centric physiological findings to females is not universally appropriate and may even be detrimental. Thus, addressing this imbalance and taking into consideration sex as a biological variable is mandatory for optimization of precision exercise interventions and/or regimens. Our present analysis focused on establishing multiomic profiles in young, exercise-naïve males (n=23) and females (n=17) at rest and following acute exercise. Sex differences were characterized at baseline and following exercise using skeletal muscle and extracellular vesicle transcriptomics, whole blood methylomics, and serum metabolomics. Sex-by-time analysis of the acute exercise response revealed notable overlap, as well as divergent molecular responses between males and females. An exploratory comparison of two combined exercise regimens (high-intensity: HITT and traditional: TRAD) was then performed using singular value decomposition, revealing latent data structures that suggest a complex dose-by-sex interaction response to exercise. These findings lay the groundwork for an understanding of key differences in responses to acute exercise exposure between sexes. This may be leveraged in designing optimal training strategies, understanding common and divergent molecular interplay guiding exercise responses, and elucidating the role of sex hormones and/or other sex-specific attributes in responses to acute and chronic exercise.

Keywords:  acute exercise; metabolomics; methylomics; sex differences; transcriptomics

DOI:  https://doi.org/10.1152/physiolgenomics.00055.2024
J Vis Exp. 2025 Feb 07.

Enzymatic Isolation of Skeletal Muscle Interstitial Extracellular Vesicles.

Yaochao Zheng, Aiden Charles Streleckis, Hongyu Chen, Yao Yao.

Extracellular vesicles (EVs) are lipid bilayer-enclosed nanoparticles released by cells to transport bioactive cargo, such as proteins, RNAs, and DNAs, for intercellular communication. Investigating EV-mediated crosstalk among cells in muscle homeostasis and diseases offers significant potential to enhance our understanding of muscle development, regeneration, and atrophy. However, current protocols for isolating skeletal muscle-derived EVs (SkM-EVs) face challenges in achieving high purity and yield, primarily due to difficulties in releasing EVs from muscle tissues without compromising cellular membranes. This article presents an efficient protocol for SkM-EV isolation, comprising mechanical detachment, enzymatic dissociation, filtration, and ultracentrifugation. These steps are optimized to enhance EV release from muscle tissues, yielding high-purity SkM-EVs. Subsequently, nano-flow cytometry, BCA assay, and Western blot assay are performed to characterize the quantity and quality of the isolated SkM-EVs. This protocol holds promise for establishing a reliable platform to obtain tissue-derived EVs for advancing basic research, disease diagnosis, and drug delivery.

DOI: https://doi.org/10.3791/67439