bims-moremu 2025-02-16 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–02–16
thirty-one papers selected by
Anna Vainshtein, Craft Science Inc.

Transcriptional regulation of autophagy in skeletal muscle stem cells.
Endurance exercise remodels skeletal muscle by suppressing Ythdf1-mediated myostatin expression.
RyR1 Is Involved in the Control of Myogenesis.
Editorial: Induced pluripotent stem cells (iPSCs) for skeletal muscle diseases.
Impact of physical activity on physical function, mitochondrial energetics, ROS production, and Ca2+ handling across the adult lifespan in men.
Polyamine metabolism dysregulation contributes to muscle fiber vulnerability in ALS.
Fork in the road: therapeutic and pathological actions for fibro-adipogenic progenitors following musculoskeletal injury.
Berberine attenuates obesity-induced skeletal muscle atrophy via regulation of FUNDC1 in skeletal muscle of mice.
Circulating Extracellular Vesicles in Alcoholic Liver Disease Affect Skeletal Muscle Homeostasis and Differentiation.
Complex Actions of FKBP12 on RyR1 Ion Channel Activity Consistent with Negative Co-Operativity in FKBP12 Binding to the RyR1 Tetramer.
Role of TGF-β/SMAD/YAP/TAZ signaling in skeletal muscle fibrosis.
Microbiota protect against frailty, loss of skeletal muscle, and maintain inflammatory tone during aging in mice.
Transcriptomic characterization of postnatal muscle maturation in mice, with a focus on myopathy-associated genes.
The Alleviative Effect of Sodium Butyrate on Dexamethasone-Induced Skeletal Muscle Atrophy.
SMURF1-Induced Ubiquitination of FTH1 Disrupts Iron Homeostasis and Suppresses Myogenesis.
Macrophage-P2X4 receptors pathway is essential to persistent inflammatory muscle hyperalgesia onset, and is prevented by physical exercise.
The link between sarcopenic obesity and Alzheimer's disease: a brain-derived neurotrophic factor point of view.
Deciphering molecular crosstalk mechanisms between skeletal muscle atrophy and KRAS-mutant pancreatic cancer: a literature review.
LMNA R482L mutation causes impairments in C2C12 myoblasts subpopulations, alterations in metabolic reprogramming during differentiation, and oxidative stress.
Research on the mechanism of resistance exercise in promoting glucose metabolic shift to regulate muscle satellite cell proliferation in type 2 diabetic rats.
Interleukin-17B is a new biomarker of human muscle regeneration in dystrophinopathies.
A reference dataset of O-GlcNAc proteins in quadriceps skeletal muscle from mice.
Skeletal muscle growth to combat diabetes and obesity: the potential role of muscle-secreted factors.
The Role of Myokines in Liver Diseases.
Knocking out p38α+p38β+p38γ is required to abort the myogenic program in C2C12 myoblasts and to impose uncontrolled proliferation.
Structure predictions of MuRF1-UBE2 complexes identify amino acid residues governing interaction selectivity for each MuRF1-E2 pair.
Preeclampsia as a Study Model for Aging: The Klotho Gene Paradigm.
From Cell Architecture to Mitochondrial Signaling: Role of Intermediate Filaments in Health, Aging, and Disease.
An mTOR paradox in sarcopenia via BCAA catabolism.
MBNL overexpression rescues cardiac phenotypes in a myotonic dystrophy type 1 heart mouse model.
Transcriptional adaptation upregulates utrophin in Duchenne muscular dystrophy.

Dis Model Mech. 2025 Feb 01. pii: DMM052007. [Epub ahead of print]18(2):

Transcriptional regulation of autophagy in skeletal muscle stem cells.

Priya D Gopal Krishnan, Wen Xing Lee, Kah Yong Goh, Sze Mun Choy, Lewin Raymarc Roldan Turqueza, Zhuo Han Lim, Hong-Wen Tang.

  Muscle stem cells (MuSCs) are essential for the regenerative capabilities of skeletal muscles. MuSCs are maintained in a quiescent state, but, when activated, can undergo proliferation and differentiation into myocytes, which fuse and mature to generate muscle fibers. The maintenance of MuSC quiescence and MuSC activation are processes that are tightly regulated by autophagy, a conserved degradation system that removes unessential or dysfunctional cellular components via lysosomes. Both the upregulation and downregulation of autophagy have been linked to impaired muscle regeneration, causing myopathies such as cancer cachexia, sarcopenia and Duchenne muscular dystrophy. In this Review, we highlight the importance of autophagy in regulating MuSC activity during muscle regeneration. Additionally, we summarize recent studies that link the transcriptional dysregulation of autophagy to muscle atrophy, emphasizing the dominant roles that transcription factors play in myogenic programs. Deciphering and understanding the roles of these transcription factors in the regulation of autophagy during myogenesis could advance the development of regenerative medicine.

Keywords:  Autophagy; Muscle diseases; Muscle regeneration; Muscle stem cells

DOI:  https://doi.org/10.1242/dmm.052007
Cell Death Dis. 2025 Feb 13. 16(1): 96

Endurance exercise remodels skeletal muscle by suppressing Ythdf1-mediated myostatin expression.

Xin Huang, Chenzhong Xu, Jie Zhang, Weiwei Wu, Zimei Wang, Qiuxiang Pang, Zuojun Liu, Baohua Liu.

Exercise can improve health via skeletal muscle remodeling. Elucidating the underlying mechanism may lead to new therapeutics for aging-related loss of skeletal muscle mass. Here, we show that endurance exercise suppresses expression of YT521-B homology domain family (Ythdf1) in skeletal muscle, which recognizes the N6-methyladenosine (m6A). Ythdf1 deletion phenocopies endurance exercise-induced muscle hypertrophy in mice increases muscle mitochondria content and type I fiber specification. At the molecular level, Ythdf1 recognizes and promotes the translation of m6A-modified Mstn mRNA, which encodes a muscle growth inhibitor, Myostatin. Loss of Ythdf1 leads to hyperactivation of skeletal muscle stem cells (MuSCs), also called satellite cells (SCs), enhancing muscle growth and injury-induced regeneration. Our data reveal Ythdf1 as a key regulator of skeletal muscle homeostasis, provide insights into the mechanism by which endurance exercise promotes skeletal muscle remodeling and highlight potential strategies to prevent aging-related muscle degeneration.

DOI: https://doi.org/10.1038/s41419-025-07379-5
Cells. 2025 Jan 21. pii: 158. [Epub ahead of print]14(3):

RyR1 Is Involved in the Control of Myogenesis.

Amandine Tourel, Robin Reynaud-Dulaurier, Julie Brocard, Julien Fauré, Isabelle Marty, Anne Petiot.

  The RyR1 calcium release channel is a key player in skeletal muscle excitation-contraction coupling. Mutations in the RYR1 gene are associated with congenital myopathies. Recently, a role of RyR1 in myotubes differentiation has been proposed and attributed to its calcium channel function, which nonetheless remains to be clearly demonstrated. In order to clarify RyR1 role in myogenesis, we have developed an in vitro model, the so-called RyR1-Rec myotubes, which are mouse primary myotubes with an inducible decrease in RyR1 protein amount and in RyR1-mediated calcium release. Using this model, we showed that the RyR1 protein decrease was responsible for an increase in both differentiation and fusion, from the RNA level to the morphological level, without affecting the myogenic factors MyoD and MyoG. Although an increase in mTOR pathway was observed in RyR1-Rec myotubes, it did not seem to be responsible for the role of RyR1 in myogenesis. Additionally, even if modulation of intracellular calcium level affected RyR1-Rec myotubes differentiation, we have shown that the role of RyR1 in myogenesis was independent of its calcium channel function. Therefore, our findings indicate that, besides its pivotal role as a calcium channel responsible for muscle contraction, RyR1 fulfills a calcium-independent inhibitor function of myogenesis.

Keywords:  RyR1; calcium; myogenesis

DOI:  https://doi.org/10.3390/cells14030158
Front Cell Dev Biol. 2025 ;13 1556403

Editorial: Induced pluripotent stem cells (iPSCs) for skeletal muscle diseases.

Hidetoshi Sakurai, Masatoshi Suzuki, Atsushi Asakura.



Keywords:  IPSC; aging; amyotrophic lateral sclerosis (ALS); muscle stem cell; muscular dystrophgies; neuromuscular diseases; satellite cell; skeletal muscle

DOI:  https://doi.org/10.3389/fcell.2025.1556403
Cell Rep Med. 2025 Feb 06. pii: S2666-3791(25)00041-2. [Epub ahead of print] 101968

Impact of physical activity on physical function, mitochondrial energetics, ROS production, and Ca2+ handling across the adult lifespan in men.

Marina Cefis, Vincent Marcangeli, Rami Hammad, Jordan Granet, Jean-Philippe Leduc-Gaudet, Pierrette Gaudreau, Caroline Trumpff, Qiuhan Huang, Martin Picard, Mylène Aubertin-Leheudre, Marc Bélanger, Richard Robitaille, José A Morais, Gilles Gouspillou.

  Aging-related muscle atrophy and weakness contribute to loss of mobility, falls, and disability. Mitochondrial dysfunction is widely considered a key contributing mechanism to muscle aging. However, mounting evidence positions physical activity as a confounding factor, making unclear whether muscle mitochondria accumulate bona fide defects with aging. To disentangle aging from physical activity-related mitochondrial adaptations, we functionally profiled skeletal muscle mitochondria in 51 inactive and 88 active men aged 20-93. Physical activity status confers partial protection against age-related decline in physical performance. Mitochondrial respiration remains unaltered in active participants, indicating that aging per se does not alter mitochondrial respiratory capacity. Mitochondrial reactive oxygen species (ROS) production is unaffected by aging and higher in active participants. In contrast, mitochondrial calcium retention capacity decreases with aging regardless of physical activity and correlates with muscle mass, performance, and the stress-responsive metabokine/mitokine growth differentiation factor 15 (GDF15). Targeting mitochondrial calcium handling may hold promise for treating aging-related muscle impairments.

Keywords:  calcium retention capacity; functional capacities; intermuscular fat accumulation; mitochondria; mitochondrial permeability transition pore; muscle atrophy and weakness; physical performance; reactive oxygen species; sarcopenia; skeletal muscle aging

DOI:  https://doi.org/10.1016/j.xcrm.2025.101968
Cell Rep. 2025 Jan 28. pii: S2211-1247(24)01474-8. [Epub ahead of print]44(1): 115123

Polyamine metabolism dysregulation contributes to muscle fiber vulnerability in ALS.

Veronica Ruggieri, Silvia Scaricamazza, Andrea Bracaglia, Chiara D'Ercole, Cristina Parisi, Paolo D'Angelo, Daisy Proietti, Chiara Cappelletti, Alberto Macone, Biliana Lozanoska-Ochser, Marina Bouchè, Lucia Latella, Cristiana Valle, Alberto Ferri, Lorenzo Giordani, Luca Madaro.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease causing progressive paralysis due to motor neuron degeneration with no curative therapy despite extensive biomedical research. One of the primary targets of ALS is skeletal muscle, which undergoes profound functional changes as the disease progresses. To better understand how altered innervation interferes with muscle homeostasis during disease progression, we generated a spatial transcriptomics dataset of skeletal muscle in the SOD1G93A mouse model of ALS. Using this strategy, we identified polyamine metabolism as one of the main altered pathways in affected muscle fibers. By establishing a correlation between the vulnerability of muscle fibers and the dysregulation of this metabolic pathway, we show that disrupting polyamine homeostasis causes impairments similar to those seen in ALS muscle. Finally, we show that restoration of polyamine homeostasis rescues the muscle phenotype in SOD1G93A mice, opening new perspectives for the treatment of ALS.

Keywords:  CP: Metabolism; CP: Neuroscience; amyotrophic lateral sclerosis; muscular atrophy; neuromuscular junction; polyamines; skeletal muscle; spatial transcriptomics

DOI:  https://doi.org/10.1016/j.celrep.2024.115123
J Physiol. 2025 Feb 11.

Fork in the road: therapeutic and pathological actions for fibro-adipogenic progenitors following musculoskeletal injury.

Allison M Owen, Sara Gonzalez-Velez, Alexander R Keeble, Nicholas T Thomas, Christopher S Fry.

  Musculoskeletal injuries are a substantial source of global disability through weakness and loss of function, which can be attributable, in part, to deficits in skeletal muscle quality. Poor muscle quality, resulting from fibrotic pathology or fatty infiltration, strongly predicts lower rates of patient recovery following injury and higher rates of re-injury. The cellular sources of fibrosis and fatty infiltration within skeletal muscle are mesenchymal fibro-adipogenic progenitors (FAPs), which are central effectors to support muscle homeostasis, regeneration and growth. However, following acute or chronic musculoskeletal injury, FAPs can promote fibro/fatty pathology within muscle that is likely to limit recovery and repair. Given their indispensable role within skeletal muscle, FAPs have emerged as a compelling cellular target to promote tissue recovery following acute and chronic injury. This review provides insight into the aetiology of FAP activity following various musculoskeletal injuries, in addition to signalling components that effect FAP differentiation. Contrasting pathology with therapeutic potential, insight into disease- and injury-specific FAP activation further cements their role as crucial effectors to improve muscle function and enhance patient outcomes.

Keywords:  anterior cruciate ligament; fibro‐adipogenic progenitor; rotator cuff; skeletal muscle; trauma

DOI:  https://doi.org/10.1113/JP286816
Sci Rep. 2025 Feb 10. 15(1): 4918

Berberine attenuates obesity-induced skeletal muscle atrophy via regulation of FUNDC1 in skeletal muscle of mice.

Yijie Wu, Yanhui Yang, Caixia Du, Xiaoyue Peng, Wenying Fan, Baocheng Chang, Chunyan Shan.

  Skeletal muscle atrophy is a complication of obesity, partially induced by impaired mitophagy. This study investigates whether Berberine(BBR) protects mice from obese skeletal muscle atrophy and the underlying molecular mechanism. Twenty C57BL/6 mice were fed a high-fat diet until they weighed more than 20% of the average body weight of the control group. The mice were then divided into two groups and gavaged with BBR or vehicle for 8 weeks. 10 mice were used as controls. Fasting blood glucose was measured, an oral glucose tolerance test was performed, and the mice were measured for grip strength and exercise capacity. H&E and Oil Red O staining were used to observe the pathological changes of skeletal muscle. MURF1, FBXO32, BAX, BCL2, P62, LC3 and mitophagy receptor FUNDC1 were observed in mice. BBR was intervened in C2C12 myotubes. The role of FUNDC1 was verified by RNA interference. We found that BBR treatment increased grip strength and improved muscle function. BBR not only reduced weight gain, excessive lipid accumulation and hyperlipidemia, but also ameliorated obesity-induced skeletal muscle atrophy and apoptosis. BBR promoted autophagy and increased FUNDC1 protein expression. The same positive effects were observed after BBR intervening on C2C12 myotubes, whereas FUNDC1 RNA interference attenuated the anti-skeletal muscle atrophy effect of BBR. These results suggest that BBR ameliorated obesity-induced skeletal muscle atrophy in mice by modulating the skeletal muscle mitophagy receptor FUNDC1, which may be a potential therapeutic target for obesity-induced skeletal muscle atrophy.

Keywords:  Berberine; FUNDC1; Mitophagy; Obesity-induced skeletal muscle atrophy

DOI:  https://doi.org/10.1038/s41598-025-89297-2
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13675

Circulating Extracellular Vesicles in Alcoholic Liver Disease Affect Skeletal Muscle Homeostasis and Differentiation.

Laura Barberi, Cristiana Porcu, Caterina Boccia, Marianna Cosentino, Carmine Nicoletti, Barbara Peruzzi, Francesca Iosi, Flavia Forconi, Giulia Bagnato, Gabriella Dobrowolny, Simone Di Cola, Lucia Lapenna, Gianluca Cera, Manuela Merli, Antonio Musarò.

   BACKGROUND: The mechanisms underlying muscle alteration associated to alcoholic liver disease (ALD) are not fully understood and the physiopathologic mediators of the liver-muscle interplay remains elusive. We investigated the role of circulating extracellular vesicles (EVs) in ALD as potential mediators of muscle atrophy.
METHODS: We established a mouse model of sarcopenia associated to ALD, by feeding mice with an alcoholic diet for 8 weeks. We investigated the effects of hepatic and circulating EVs isolated from these mice (EtOH mice; n = 7 females) on muscle cell cultures, comparing them with EVs from mice fed with a standard diet (CD mice; n = 6 females). Additionally, we examined the impact of circulating EVs from patients with alcohol-related cirrhosis (7 males and 2 females, mean age 55.4 years) on primary human muscle cells, comparing them with EVs from age-matched healthy subjects (6 males and 3 females). We analysed the miRNA profile of the EVs to identify potential mediators of ALD-associated sarcopenia.
RESULTS: We demonstrated that circulating EVs were internalized by muscle cells and that EVs from ALD mice and cirrhotic patients caused alteration in the myogenic program. Molecular analysis revealed that serum EVs from ALD mice reduced protein synthesis in C2C12 cells, decreasing levels of p-AKT/AKT (-54.6%; p < 0.05), p-mTOR/mTOR (-54.5%; p < 0.05) and p-GSK3(Ser9)/GSK3 (-30.63%). Similarly, hepatic EVs induced defects in muscle differentiation, with reduced levels of p-AKT/AKT (-39.1%; p < 0.05), p-mTOR/mTOR (-30.1%; p < 0.05) and p-GSK3(Ser9)/GSK3 (-40%). C2C12 cells treated with either serum or hepatic EtOH-EVs exhibited upregulated expression of muscle-specific atrophy markers Atrogin-1 (+61.2% and +189.5%, respectively; p < 0.05) and MuRF1 (+260.4% and +112.5%, respectively; p < 0.05), along with an increased LC3-II/-I ratio (+131.5% and +40.2%, respectively; p < 0.05), indicating enhanced autophagy. MiRNA analysis revealed that both circulating and hepatic EVs from ALD mice showed elevated expression of miR-21, miR-155, miR-223 and miR-122 (+230% and +292%, respectively; p < 0.01) suggesting their potential role in sarcopenia. Human muscle cells exposed to EVs from cirrhotic patients exhibited reduced protein synthesis and upregulated Atrogin-1 (+113%; p < 0.05) and MuRF1 (+86.3%; p < 0.05), indicating proteasome activation. Circulating EVs of alcoholic patients showed upregulation of the same miRNAs observed in EtOH mice, including the liver-specific miR-122 (+260%; p < 0.05) suggesting, also in human liver disease, a hepatic origin of circulating EVs.
CONCLUSIONS: Our study highlights the critical role of ALD-derived circulating EVs in affecting muscle homeostasis and myogenic program, suggesting potential therapeutic targets for mitigating muscle loss in ALD.

Keywords:  alcoholic liver disease (ALD); extracellular vesicles (EVs); liver‐muscle interplay; microRNA (miRNA); muscle atrophy; sarcopenia

DOI:  https://doi.org/10.1002/jcsm.13675
Cells. 2025 Jan 21. pii: 157. [Epub ahead of print]14(3):

Complex Actions of FKBP12 on RyR1 Ion Channel Activity Consistent with Negative Co-Operativity in FKBP12 Binding to the RyR1 Tetramer.

Spencer J Richardson, Chris G Thekkedam, Marco G Casarotto, Nicole A Beard, Angela F Dulhunty.

  The association of the 12 KDa FK506 binding protein (FKBP12) with ryanodine receptor type 1 (RyR1) in skeletal muscle is thought to suppress RyR1 channel opening and contribute to healthy muscle function. The strongest evidence for this role is increased RyR1 channel activity following FKBP12 dissociation. However, the corollary that channel activity will decrease when FKBP12 is added back to FKBP12-depleted RyR1 is not well established, and when reported, the time- and concentration-dependence of inhibition vary over orders of magnitude. Here, we address this problem with an investigation of the molecular mechanisms of the FKBP12 regulation of RyR1. Muscle processing to obtain sarcoplasmic reticulum (SR) vesicle preparations enriched in RyR1 resulted in substantial FKBP12 dissociation from RyR1, indicating low-affinity binding. Conversely, high-affinity binding was indicated by some FKBP12 remaining bound to RyR1 after solubilization. We report, for the first time, an increase in the activity of FKBP12-depleted channels after the addition of exogenous FKBP12 (5 nM to 5 µM), followed by a reduction in activity consistent with inhibition after 20-30 min exposure to higher [FKBP12]s. Both the increase and later decline in activity were time- and concentration-dependent. The results suggest a high-affinity activation when FKBP12 binding sites on the RyR1 tetramer are partially occupied by FKBP12 and lower affinity inhibition as more RyR1 monomers become occupied. These novel results imply negative cooperativity in FKBP12 binding to RyR1 and a dynamic role for FKBP12/RyR1 interactions in intact muscle fibers.

Keywords:  FKBP12; ion channel activation; ion channel inhibition; myopathy; ryanodine receptor; skeletal muscle

DOI:  https://doi.org/10.3390/cells14030157
Am J Physiol Cell Physiol. 2025 Feb 10.

Role of TGF-β/SMAD/YAP/TAZ signaling in skeletal muscle fibrosis.

Felipe S Gallardo, Meilyn Cruz-Soca, Alexia Bock-Pereda, Jennifer Faundez-Contreras, Cristian Gutiérrez-Rojas, Alessandro Gandin, Veronica Torresan, Juan Carlos Casar, Andrea Ravasio, Enrique Brandan.

  Skeletal muscle fibrosis is strongly associated with the differentiation of its resident multipotent fibro/adipogenic progenitors (FAPs) towards the myofibroblast phenotype. Although TGF-β signaling is well-known for driving FAPs differentiation and fibrosis, due to its pleiotropic functions its complete inhibition is not suitable for treating fibrotic disorders such as muscular dystrophies. Here, we describe that TGF-β operates through the mechanosensitive transcriptional regulators YAP/TAZ to determine the myofibroblast fate of FAPs and skeletal muscle fibrosis. Spatial transcriptomics analyses of dystrophic and acute injured muscles showed that areas with active fibrosis and TGF-β signaling displayed high YAP/TAZ activity. Using a TGF-β-driven fibrotic mouse model, we found that activation of YAP/TAZ in activated FAPs is associated with the fibrotic process. Mechanistically, primary culture of FAPs reveals the remarkable ability of TGF-β1 to activate YAP/TAZ through its canonical SMAD3 pathway. Moreover, inhibition of YAP/TAZ, either by disrupting its activity (with Verteporfin) or cellular mechanotransduction (with the Rho inhibitor C3 or soft matrices), decreased TGF-β1-dependent FAPs differentiation into myofibroblasts. In vivo, administration of Verteporfin in mice limits the deposition of collagen and fibronectin, and the activation of FAPs during the development of fibrosis. Overall, our work provides robust evidence for considering YAP/TAZ as a potential target in muscular fibroproliferative disorders.

Keywords:  FAPs; Fibrosis; Skeletal muscle; TGF-beta; YAP/TAZ

DOI:  https://doi.org/10.1152/ajpcell.00541.2024
Am J Physiol Cell Physiol. 2025 Feb 10.

Microbiota protect against frailty, loss of skeletal muscle, and maintain inflammatory tone during aging in mice.

Meghan O Conn, Erica N DeJong, Daniel M Marko, Russta Fayyazi, Dana Kukje Zada, Kevin P Foley, Nicole G Barra, Dawn M E Bowdish, Jonathan D Schertzer.

  Chronic low-level inflammation or "inflammaging" is hypothesized to contribute to sarcopenia and frailty. Resident microbiota are thought to promote inflammaging, frailty, and loss of skeletal muscle mass. We tested immunity and frailty in male C57BL6/N germ-free (GF), specific-pathogen-free (SPF), and mice that were born germ-free and colonized (COL) with an SPF microbiota. Male and female GF mice had lower systemic cellular inflammation indicated by lower blood Ly6Chigh monocytes across their lifespan. Male GF mice had lower body mass, but relative to body mass, GF mice had smaller hindlimb muscles and smaller muscle fibers compared to SPF mice across the lifespan. Male and female GF mice had increased frailty at 18 months or older. Colonization of female GF mice increased blood Ly6Chigh monocytes, but did not affect frailty at 18 months or older. Colonization of male GF mice increased blood Ly6Chigh monocytes, skeletal muscle size, myofiber fiber size, and decreased frailty at 18 months or older. Transcriptomic analysis of the tibialis anterior muscle revealed a microbiota-muscle axis with over 550 differentially expressed genes in COL male mice at 18 months or older. Colonized male mice had transcripts indicative of lower tumor necrosis factor-alpha (TNF) signaling via nuclear factor κB (NF-κB). Our findings show that microbiota can increase systemic cellular immunity, while decreasing muscle inflammation, thereby protecting against muscle loss and frailty. We also found sex differences in the role of microbiota regulating frailty. We propose that microbiota components protect against lower muscle mass and frailty across the lifespan in mice.

Keywords:  Aging; Gut Microbiota; Muscle; Sarcopenia

DOI:  https://doi.org/10.1152/ajpcell.00869.2024
Dis Model Mech. 2025 Feb 13. pii: dmm.052098. [Epub ahead of print]

Transcriptomic characterization of postnatal muscle maturation in mice, with a focus on myopathy-associated genes.

Alix Simon, Sarah Djeddi, Pauline Bournon, David Reiss, Julie Thompson, Jocelyn Laporte.

  Gene differential expression (DE) and alternative splicing (AS) are mechanisms that give rise to a plethora of tissue-specific transcripts. While these mechanisms have been studied in various tissues, their role during muscle maturation is not well understood. Since this stage of development is impaired in multiple muscular diseases, we used RNA-seq to analyze transcriptome remodeling in skeletal muscle from late embryonic stage (E18.5) to adult mouse (7 weeks). Major transcriptomic changes were detected, especially in the first two weeks after birth with a total of 8571 DE genes and 3096 AS genes. Comparison of these two mechanisms showed that they regulate different biological processes essential for the structure and function of skeletal muscle. Investigation of genes mutated in muscle disorders revealed previously unknown transcripts. In particular, we validated a novel exon in Lrp4, a gene mutated in congenital myasthenia, in mice and human. Overall, the characterization of the transcriptome in disease-relevant tissues revealed key pathways in the regulation of tissue maturation and function. Importantly, the exhaustive description of AS and resulting transcripts can improve genetic diagnosis.

Keywords:  Alternative splicing; Differential expression; Lrp4; Myopathy; Skeletal muscle maturation

DOI:  https://doi.org/10.1242/dmm.052098
Cell Biol Int. 2025 Feb 12.

The Alleviative Effect of Sodium Butyrate on Dexamethasone-Induced Skeletal Muscle Atrophy.

Xingchen Zhao, Mingqiang Zhu, Zifan Wang, Ming Gao, Yifei Long, Shuo Zhou, Wei Wang.

  Skeletal muscle mass is significantly negatively regulated by glucocorticoids. Following glucocorticoid administration, the balance between protein synthesis and breakdown in skeletal muscle is disrupted, shifting towards a predominance of catabolic metabolism. Short-chain fatty acids like sodium butyrate have been found to regulate inflammatory reactions and successively activate signaling pathways. The preventive benefits of sodium butyrate against dexamethasone-induced skeletal muscle atrophy and myotube atrophy models were examined in this work, and the underlying mechanism was clarified. A total of 32 6-week-old C57BL/6 inbred male mice were randomly assigned to one of four groups and treated with dexamethasone to induce muscle atrophy and sodium butyrate. We found that sodium succinate alleviated dexamethasone-induced myotube atrophy in the myotube atrophy model by lowering the gene expression of two E3 ubiquitin ligases, Atrogin-1 and MURF1, and activating the AKT/mTOR signaling pathway. Pertussis toxin reversed this effect, indicating that G protein-coupled receptors were involved in sodium butyrate's action as a mediator. Additionally, pre-treatment with sodium butyrate lowered weight and muscle mass loss in a mouse model of skeletal muscle atrophy, dramatically decreased the MURF1 gene expression and decreased the nuclear translocation of the glucocorticoid receptor. In conclusion, this study shows that sodium butyrate inhibits the expression of atrophy genes, thus preventing the breakdown of proteins and the loss of muscle mass, while also inhibiting weight loss, in animal models.

Keywords:  dexamethasone; skeletal muscle atrophy; sodium butyrate

DOI:  https://doi.org/10.1002/cbin.70003
Int J Mol Sci. 2025 Feb 06. pii: 1390. [Epub ahead of print]26(3):

SMURF1-Induced Ubiquitination of FTH1 Disrupts Iron Homeostasis and Suppresses Myogenesis.

Xia Xiong, Wen Li, Chunlin Yu, Mohan Qiu, Zengrong Zhang, Chenming Hu, Shiliang Zhu, Li Yang, Han Pen, Xiaoyan Song, Jialei Chen, Bo Xia, Shunshun Han, Chaowu Yang.

  Ferritin heavy chain 1 (FTH1) is pivotal in the storage, release, and utilization of iron, plays a crucial role in the ferroptosis pathway, and exerts significant impacts on various diseases. Iron influences skeletal muscle development and health by promoting cell growth, ensuring energy metabolism and ATP synthesis, maintaining oxygen supply, and facilitating protein synthesis. However, the precise molecular mechanisms underlying iron's regulation of skeletal muscle growth and development remain elusive. In this study, we demonstrated that the conditional knockout (cKO) of FTH1 in skeletal muscle results in muscle atrophy and impaired exercise endurance. In vitro studies using FTH1 cKO myoblasts revealed notable decreases in GSH concentrations, elevated levels of lipid peroxidation, and the substantial accumulation of Fe2+, collectively implying the induction of ferroptosis. Mechanistically, E3 ubiquitin-protein ligase SMURF1 (SMURF1) acts as an E3 ubiquitin ligase for FTH1, thereby facilitating the ubiquitination and subsequent degradation of FTH1. Consequently, this activation of the ferroptosis pathway by SMURF1 impedes myoblast differentiation into myotubes. This study identifies FTH1 as a novel regulator of muscle cell differentiation and skeletal muscle development, implicating its potential significance in maintaining skeletal muscle health through the regulation of iron homeostasis.

Keywords:  FTH1; SMURF1; ferroptosis; iron homeostasis; skeletal muscle; ubiquitination

DOI:  https://doi.org/10.3390/ijms26031390
PLoS One. 2025 ;20(2): e0318107

Macrophage-P2X4 receptors pathway is essential to persistent inflammatory muscle hyperalgesia onset, and is prevented by physical exercise.

Graciana de Azambuja, Fernando Moreira Simabuco, Maria Cláudia Gonçalves de Oliveira.

Peripheral inflammation may lead to severe inflammatory painful conditions. Macrophages are critical for inflammation; modulating related pathways could be an essential therapeutic strategy for chronic pain diseases. Here we hypothesized that 1) Macrophage-P2X4 receptors are involved in the transition from acute to persistent inflammatory muscle hyperalgesia and that 2) P2X4 activation triggers a pro-inflammatory phenotype leading to Interleukin-1β (IL-1β) increase. Once physical exercise prevents exacerbated inflammatory processes related to chronic diseases including chronic muscle pain, we also hypothesized that 3) physical exercise, through PPARγ receptors, prevents P2X4 receptors activation. With pharmacological behaviour, biomolecular analysis and swimming physical exercise in a mouse model of persistent inflammatory muscle hyperalgesia we demonstrated that P2X4 receptors are essential for transitioning from acute to persistent inflammatory muscle hyperalgesia; Phosphorylation of p38MAPK indicated P2X4 signalling activation associated with inflammatory macrophage and an increase of IL-1β expression in skeletal muscle; Exercise-PPARγ receptors prevented phosphorylation of p38MAPK in muscle tissue. Our findings suggest that exercise-PPARγ modulates the acute inflammatory phase of developing persistent muscle hyperalgesia by controlling p38MAPK-related P2X4 signalling. These highlight the great potential of modulating macrophage phenotypes and P2X4 receptors to prevent pain conditions and the ability of physical exercise to prevent inflammatory processes related to chronic muscle pain.

DOI: https://doi.org/10.1371/journal.pone.0318107
J Physiol. 2025 Feb 12.

The link between sarcopenic obesity and Alzheimer's disease: a brain-derived neurotrophic factor point of view.

Emily N Copeland, Paul J LeBlanc, Paula Duarte-Guterman, Val A Fajardo, Rebecca E K MacPherson.

  Age-related diseases are becoming more prominent as the lifespan of the global population rises. Many of these diseases coincide with each other and can even influence the onset of additional comorbidities. Sarcopenic obesity is described as age-related loss of muscle mass that concurs with excessive weight gain and tends to increase the risk of comorbidity development, including Alzheimer's disease (AD). Though the exact link between sarcopenic obesity and AD is not known, this review explores the possibility that reduced levels of brain-derived neurotrophic factor (BDNF) throughout the body may serve as the underlying commonality. In AD, reductions in BDNF signalling through its receptor promote the activation of glycogen synthase kinase 3 beta (GSK3β), which subsequently increases the production of amyloid beta (Aβ) peptides and neurofibrillary tangles (NFTs). In the skeletal muscle, lower BDNF concentrations are linked to impaired muscle fibre repair and regeneration, increasing the likelihood of sarcopenia. Furthermore, the absence of BDNF impairs mitochondrial function, leading to insulin resistance and increased adiposity. BDNF concentration has a negative relationship with obesogenic markers in adipose tissue, and as such, lower concentrations of BDNF lead to weight gain. Collectively, current literature suggests that BDNF attenuates AD pathology while improving skeletal muscle mitochondrial function, whole-body insulin resistance and facilitating adipocyte browning. Therefore, BDNF may be a viable target for multiple age-related diseases, but more research is required to substantiate this claim, with a particular focus on examining any potential influence of biological sex, as women are at a higher risk for both AD and sarcopenic obesity.

Keywords:  adipose tissue; ageing; brain; crosstalk; skeletal muscle

DOI:  https://doi.org/10.1113/JP288032
Hepatobiliary Surg Nutr. 2025 Feb 01. 14(1): 78-95

Deciphering molecular crosstalk mechanisms between skeletal muscle atrophy and KRAS-mutant pancreatic cancer: a literature review.

Yuquan Guo, Siyang Han, Weisheng Yu, Yaolin Xu, Ying Ying, Huaxiang Xu, Haokang Feng, Xu'an Wang, Wenchuan Wu, Dansong Wang, Liang Liu, Xu Han, Wenhui Lou.

   Background and Objective: Cachexia-induced skeletal muscle atrophy is a critical manifestation in Kirsten rat sarcoma viral oncogene homologue (KRAS)-mutant pancreatic cancer (PC) patients, predominantly characterized by a shift in metabolic equilibrium towards catabolism that accelerates protein degradation in myofibers and leads to muscle atrophy. This metabolic reprogramming not only supports tumor growth but also precipitates energy depletion in skeletal muscle tissues. Exploring these mechanisms reveals potential therapeutic targets in the metabolic and proteolytic pathways associated with KRAS-mutant PC.
Methods: A comprehensive search for literature was conducted in PubMed, Web of Science, Google Scholar and other search engines up to May 21st, 2024. Studies on PC models and patients were included.
Key Content and Findings: The crosstalk between KRAS-mutant PC and skeletal muscle atrophy can be categorized into four principal domains: (I) KRAS-driven metabolic reprogramming in cancer cells leads to the depletion of muscle energy reserves, thereby influencing the reallocation of myofiber energy towards fueling cancer cell; (II) KRAS-mutant cancer cells rely on nutrient-scavenging pathways, resulting in altered cytokine profiles, increased ubiquitin mRNA expression and autophagy-lysosome pathway, which facilitate myotube degradation and inhibit muscle regeneration, thereby disrupting muscular homeostasis and causing a one-way nutrient flux; (III) tumor-induced oxidative stress inflicts damage on myotubes, highlighting the detrimental effects of reactive oxygen species on muscle structure; (IV) KRAS-mutant cancer cells remodulate immune cell dynamics within the tumor environment, thereby reshaping host immunity. Together, these findings illuminate the intricate interplay between KRAS-mutant PC and skeletal muscle atrophy, mapping the pathophysiological framework that is crucial for understanding sarcopenia and related disorders.
Conclusions: This comprehensive analysis advances our understanding of the complex etiology of cancer cachexia and stimulates the development of targeted therapeutic strategies.

Keywords:  Kirsten rat sarcoma viral oncogene homologue-mutant (KRAS-mutant); Skeletal muscle atrophy; cachexia; molecular crosstalk; pancreatic cancer (PC)

DOI:  https://doi.org/10.21037/hbsn-24-282
Sci Rep. 2025 Feb 13. 15(1): 5358

LMNA R482L mutation causes impairments in C2C12 myoblasts subpopulations, alterations in metabolic reprogramming during differentiation, and oxidative stress.

Oksana A Ivanova, Alexander V Predeus, Margarita Y Sorokina, Elena V Ignatieva, Danila E Bobkov, Kseniia S Sukhareva, Anna A Kostareva, Renata I Dmitrieva.

LMNA mutations causing classical familial partial lipodystrophy of Dunnigan type (FPLD2) usually affect residue R482. FPLD is a severe metabolic disorder that often leads to cardiovascular and skeletal muscle complications. How LMNA mutations affect the functional properties of skeletal muscles is still not well understood. In the present project, we investigated the LMNA-R482L mutation-specific alterations in a transgenic mouse C2C12 cell line of myoblasts. Using single-cell RNA sequencing we have studied transcriptional diversity of cultured in vitro C2C12 cells. The LMNA-R482L mutation induces changes in C2C12 cluster composition and increases the expression of genes related to connective tissue development, oxidative stress, stress defense, and autophagy in a population-specific manner. Bulk RNA-seq confirmed these results and revealed the dysregulation of carbohydrate metabolism in differentiated R482L myotubes that was supported by ATP production profile evaluation. The measurement of reactive oxygen species (ROS) levels and glutathione accumulation in myoblasts and myotubes indicates R482L mutation-related dysregulation in mechanisms that control ROS production and scavenging through antioxidant glutathione system. The increased accumulation of autophagy-related structures in R482L myoblasts was also shown. Overall, our experiments showed a connection between the redox status and metabolic alterations with skeletal muscle pathological phenotypes in cells bearing pathogenic LMNA mutation.

DOI: https://doi.org/10.1038/s41598-025-88219-6
Biochem Biophys Res Commun. 2025 Jan 30. pii: S0006-291X(25)00115-9. [Epub ahead of print]751 151401

Research on the mechanism of resistance exercise in promoting glucose metabolic shift to regulate muscle satellite cell proliferation in type 2 diabetic rats.

Ying Li, Ningwen Xiao, Qian Wang, Bo Liu, Ying Cui, Yanyan Liu, Ying Ji, Mi Zheng.

  Skeletal muscle atrophy is a common complication in patients with type 2 diabetes (T2D) and is associated with dysfunction of muscle satellite cells. The activation and proliferation of muscle satellite cells involve a switch in glucose metabolism, which is regulated by driving the acetylation of histones to control the expression of related genes. Studies have confirmed that resistance exercise can improve insulin resistance and activate muscle satellite cells, but the specific molecular mechanisms are not yet clear. This study aims to investigate whether resistance exercise can promote the proliferation of muscle satellite cells and improve muscle atrophy in type 2 diabetic rats by enhancing glucose metabolism in skeletal muscles. A T2D rat model was induced by combining a high-fat diet with streptozotocin injection. After 8 weeks of resistance exercise, the activity of key enzymes (Pyruvate Kinase, Phosphofructokinase, Pyruvate Dehydrogenase) in glucose metabolism in the skeletal muscles of T2D rats significantly increased, the expression of Sirtuin 1 (Sirt1) and Nicotin -amide Phosphoribosyltransferase (Nampt) in the skeletal muscles of the rats decreased, and the expression of acetylation of lysine 16 on histone H4 (H4K16ac) significantly increased, indicating an elevated level of the H4K16ac. The expression of paired box 7 (Pax7) and myogenic differentiation (MyoD) was significantly upregulated, indicating that exercise promoted the proliferation of muscle satellite cells. These results suggest that resistance exercise may promote glucose metabolism in skeletal muscles of T2D rats by regulating the activity of key enzymes in sugar metabolism, further regulating Sirt1-mediated histone H4K16ac, thereby promoting the proliferation of muscle satellite cells and improving muscle atrophy.

Keywords:  Glucose metabolism; Histone acetylation; Muscle satellite cells; Resistance exercise; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.bbrc.2025.151401
Brain. 2025 Feb 11. pii: awaf058. [Epub ahead of print]

Interleukin-17B is a new biomarker of human muscle regeneration in dystrophinopathies.

Chang Liu, Zhihao Xie, Qingyue Yuan, Yanyu Lu, Jianwen Deng, Zhaoxia Wang, Lingchao Meng, Yun Yuan, Zhiying Xie.

  We aimed to identify novel biomarkers of muscle pathological changes via a large-scale histopathology-based multi-omics study of dystrophinopathies. We performed a comparative pathological analysis of 121 Duchenne muscular dystrophy (DMD) and 114 Becker muscular dystrophy (BMD) patients to determine muscle pathological similarities and differences between DMD and BMD that have not been systematically investigated. Customized bioinformatic analyses of bulk muscle RNA-sequencing data derived from 35 DMD patients, 39 BMD patients, and 21 controls were performed to identify gene signatures associated with pathological changes. Validation experiments, including single-nucleus RNA-sequencing, RNAscope in situ hybridization, and immunofluorescence staining, were performed in a subset of DMD and BMD patients, as well as 27 patients with other acquired and inherited myopathies. Systematic pathological analyses revealed that the percentages of necrotic, regenerating, and hypercontractive myofibers and the degree of muscle fibrosis were greater in DMD patients than in BMD patients. In both DMD and BMD patients, the percentages of necrotic, regenerating, and hypercontractive myofibers respectively increased in the early-stage and decreased in later disease stages, whereas muscle fibrosis progressively worsened with disease progression. Comparative transcriptomic analysis indicated that inflammatory responses were significantly activated in DMD patients compared to BMD patients, which was confirmed by immunohistochemistry analyses. Our customized bioinformatic analyses identified the gene set of MYH3, MYH8, IL17B, TNNT2, MYMK, and TDO2 as the most associated gene signature for muscle necrosis and regeneration. Muscle quantitative reverse transcription-polymerase chain reaction analyses confirmed significantly increased levels of IL17B and TNNT2 mRNA expression in both DMD and BMD patients compared to controls. Muscle IL17B mRNA expression was significantly correlated with histological muscle regeneration and negatively correlated with the age of patients with dystrophinopathy. Single-nucleus RNA-sequencing and RNAscope in situ hybridization demonstrated that IL17B mRNA was expressed in regenerating myofibers of patients with DMD and BMD, as well as in various acquired and inherited myopathies. Immunofluorescence staining further confirmed that interleukin-17B was expressed in regenerating myofibers of DMD and BMD patients. Our study provides evidence that interleukin-17B is a new biomarker of muscle regeneration in dystrophinopathies.

Keywords:  Becker muscular dystrophy; Duchenne muscular dystrophy; biomarker; muscle regeneration; pathology; transcriptome

DOI:  https://doi.org/10.1093/brain/awaf058
Glycobiology. 2025 Feb 10. pii: cwaf005. [Epub ahead of print]

A reference dataset of O-GlcNAc proteins in quadriceps skeletal muscle from mice.

Ruchi Jaiswal, Yimin Liu, Michael Petriello, Xiangmin Zhang, Zhengping Yi, Charlie Fehl.

  A key nutrient sensing process in all animal tissues is the dynamic attachment of O-linked N-acetylglucosamine (O-GlcNAc). Determining the targets and roles of O-GlcNAc glycoproteins has the potential to reveal insights into healthy and diseased metabolic states. In cell studies, thousands of proteins are known to be O-GlcNAcylated, but reference datasets for most tissue types in animals are lacking. Here, we apply a chemoenzymatic labeling study to compile a high coverage dataset of quadriceps skeletal muscle O-GlcNAc glycoproteins from mice. Our dataset contains over 550 proteins, and > 80% of the dataset matched known O-GlcNAc proteins. This dataset was further annotated via bioinformatics, revealing the distribution, protein interactions, and gene ontology (GO) functions of these skeletal muscle proteins. We compared these quadriceps glycoproteins with a high-coverage O-GlcNAc enrichment profile from mouse hearts and describe the key overlap and differences between these tissue types. Quadriceps muscles can be used for biopsies, so we envision this dataset to have potential biomedical relevance in detecting aberrant glycoproteins in metabolic diseases and physiological studies. This new knowledge adds to the growing collection of tissues with high-coverage O-GlcNAc profiles, which we anticipate will further the systems biology of O-GlcNAc mechanisms, functions, and roles in disease.

Keywords:  O-GlcNAc; glycoproteomics; mouse quadriceps; skeletal muscle; tissue atlas

DOI:  https://doi.org/10.1093/glycob/cwaf005
Obesity (Silver Spring). 2025 Feb 13.

Skeletal muscle growth to combat diabetes and obesity: the potential role of muscle-secreted factors.

Mitchell J Sammut, Benjamin R Thorne, C W James Melling.

As the prevalence of obesity and metabolic disease continues to climb, the need for effective therapeutic interventions remains high. The growth of skeletal muscle (SkM) greatly influences systemic metabolism across the whole body, making this tissue an important therapeutic target to combat the rise of metabolic dysfunction. Transgenic rodent models of targeted SkM growth exhibit profound improvements in various remote tissues, including adipose tissue and the liver. It is currently unclear how selective stimulation of SkM growth alters the metabolism of distant tissues; however, evidence suggests that muscle-secreted factors may be involved. Here, we aim to provide basic biomedical researchers with a summary of the current knowledge regarding various muscle-secreted factors regulated by anabolic pathways and proteins in SkM, as well as their systemic metabolic effects, to implicate them in the whole-body metabolic effects of SkM growth. In this review, we also identify several knowledge gaps in this field, future directions of investigation, and implications for therapeutic interventions such as resistance exercise and pharmacology.

DOI: https://doi.org/10.1002/oby.24223
Int J Mol Sci. 2025 Jan 25. pii: 1043. [Epub ahead of print]26(3):

The Role of Myokines in Liver Diseases.

Hiroki Nishikawa, Soo Ki Kim, Akira Asai.

  Myokine is a general term for hormones, peptides, and other substances secreted by skeletal muscle. Myokine has attracted much attention in recent years as a key substance for understanding the mechanism of "exercise and health". Skeletal muscle accounts for about 40% of the total human weight and is now recognized as an endocrine organ that produces myokines, which have physiological activity. Representative myokines include IL-6, myostatin, irisin, brain-derived neurotropic factor, fibroblast growth factor-21, and decorin. On the other hand, sarcopenia, defined by quantitative and qualitative loss of skeletal muscle, is a condition that has received much attention in recent years because of its close correlation with prognosis. In patients with chronic liver disease (CLD), sarcopenia is a common complication. Mechanisms underlying sarcopenia in CLD patients have been reported to involve protein-energy malnutrition, which is characteristic of patients with cirrhosis, signaling involved in protein synthesis and degradation, myokines such as myostatin and decorin, the ubiquitin-proteasome pathway, sex hormones such as testosterone, dysbiosis, and insulin resistance, etc., in addition to aging. Each of these pathological conditions is thought to be intricately related to each other, leading to sarcopenia. This review will summarize the relationship between CLD and myokines.

Keywords:  IL-6; liver; muscle–gut–liver axis; myokine; myostatin; sarcopenia

DOI:  https://doi.org/10.3390/ijms26031043
J Biol Chem. 2025 Feb 06. pii: S0021-9258(25)00129-2. [Epub ahead of print] 108281

Knocking out p38α+p38β+p38γ is required to abort the myogenic program in C2C12 myoblasts and to impose uncontrolled proliferation.

Navit Mooshayef, Nechama Gilad, Manju P Mohanam, David Engelberg.

The p38 MAPKs' family includes four isoforms, of which only p38α has been considered essential for numerous important processes including mice embryogenesis. It is also considered essential for myoblast to myotube differentiation, as exposure of myoblasts to p38α/β inhibitors or to siRNA that targets p38α suppresses the process. The functions of p38β and p38γ in myoblast differentiation are not clear. We knocked out p38α in C2C12 myoblasts, assuming that the resulting C2p38α-/- cells would not differentiate. They did, however, form mature fibers. We found elevated levels and activation of the p38 activator MKK6 in the C2p38α-/- cells, leading to activation of p38β and p38γ, which are not active in differentiating parental C2C12 cells. Thus, p38α is an inhibitor of p38β+p38γ, that perhaps replace it in promoting differentiation. To test this notion, we generated C2p38α/γ-/- and C2p38α/β-/- cells and found that in both clones, the myogenic program was induced. C2p38β/γ-/- cells also formed myotubes. These observations could be interpreted in two ways: either each p38 isoform can promote, by itself, the myogenic program, or p38 activity is not required at all for the process. Generating C2p38α/β/γ-/- cells in which the myogenic program was shut-off altogether, showed that p38 activity is critical for differentiation. Notably, C2p38α/β/γ-/- cells proliferate uncontrollably and give rise to foci, reminiscence of oncogenically-transformed cells. In summary, our study shows that a crosstalk between p38 isoforms functions in C2C12 cells as a safeguard mechanism that ensures resilience of the p38 activity in promoting the myogenic program and enforcing cell cycle arrest.

DOI: https://doi.org/10.1016/j.jbc.2025.108281
FEBS J. 2025 Feb 10.

Structure predictions of MuRF1-UBE2 complexes identify amino acid residues governing interaction selectivity for each MuRF1-E2 pair.

Agnès Claustre, Mélodie Malige, Maëlys Macheton, Lydie Combaret, Etienne Lefai, Pierre Fafournoux, Daniel Taillandier, Julien Henri, Cécile Polge.

  The RING-type E3 ubiquitin-protein ligase MuRF1 (also known as TRIM63) plays an important role in skeletal muscle atrophy by targeting contractile proteins. In cellulo, MuRF1 can alternatively interact with four E2 enzymes (UBE2E1, UBE2J1, UBE2J2, or UBE2L3), suggesting different functions or targets for the four MuRF1-E2 complexes. In this article, we studied the interface of these MuRF1-UBE2 complexes based on AlphaFold2 and AlphaFold3 predictions. These predictions revealed the involvement of different residues at the interface of each complex. We confirmed this overall interface difference by the differential sensitivity of MuRF1-E2 complexes to regenerating solutions in surface plasmon resonance experiments. We further confirmed several predictions individually by affinity measurements with point-mutant E2 enzymes and truncated MuRF1. We used the interaction-induced fluorescence change approach with fluorescent MuRF1. Besides canonical E2-RING-type E3 interactions, we were able to identify selective contact points between MuRF1 and its UBE2 partners. Furthermore, in the case of the MuRF1-E2E1 pair, unlike the other MuRF1-E2 pairs, the interaction may also be governed by a domain outside the RING domain. Since the function of RING-type E3s is regulated by E2 enzymes, deciphering the mechanisms of selective recruitment of E2s by MuRF1 paves the way for the development of targeted therapeutics to fight muscle atrophy.

Keywords:  MuRF1/TRIM63; RING‐type E3 ligase; UBE2; protein–protein interaction selectivity; ubiquitin

DOI:  https://doi.org/10.1111/febs.70017
Int J Mol Sci. 2025 Jan 22. pii: 902. [Epub ahead of print]26(3):

Preeclampsia as a Study Model for Aging: The Klotho Gene Paradigm.

Monia Cecati, Stefania Fumarola, Salvatore Vaiasicca, Laura Cianfruglia, Arianna Vignini, Stefano Raffaele Giannubilo, Monica Emanuelli, Andrea Ciavattini.

  Aging and pregnancy are often considered opposites in a woman's biological timeline. Aging is defined by a gradual decline in the functional capabilities of an organism over its lifetime, while pregnancy is characterized by the presence of the transient placenta, which fosters the cellular fitness necessary to support fetal growth. However, in the context of preeclampsia, pregnancy and aging share common hallmarks, including clinical complications, altered cellular phenotypes, and heightened oxidative stress. Furthermore, women with pregnancies complicated by preeclampsia tend to experience age-related disorders earlier than those with healthy pregnancies. Klotho, a gene discovered fortuitously in 1997 by researchers studying aging mechanisms, is primarily expressed in the kidneys but also to a lesser extent in several other tissues, including the placenta. The Klotho protein is a membrane-bound protein that, upon cleavage by ADAM10/17, is released into the circulation as soluble Klotho (sKlotho) where it plays a role in modulating oxidative stress. This review focuses on the involvement of sKlotho in the development of preeclampsia and age-related disorders, as well as the expression of the recently discovered Mytho gene, which has been associated with skeletal muscle atrophy.

Keywords:  Klotho; age-related disorders; aging; epigenetics; preeclampsia

DOI:  https://doi.org/10.3390/ijms26030902
Int J Mol Sci. 2025 Jan 27. pii: 1100. [Epub ahead of print]26(3):

From Cell Architecture to Mitochondrial Signaling: Role of Intermediate Filaments in Health, Aging, and Disease.

Emanuele Marzetti, Rosa Di Lorenzo, Riccardo Calvani, Vito Pesce, Francesco Landi, Hélio José Coelho-Júnior, Anna Picca.

  The coordination of cytoskeletal proteins shapes cell architectures and functions. Age-related changes in cellular mechanical properties have been linked to decreased cellular and tissue dysfunction. Studies have also found a relationship between mitochondrial function and the cytoskeleton. Cytoskeleton inhibitors impact mitochondrial quality and function, including motility and morphology, membrane potential, and respiration. The regulatory properties of the cytoskeleton on mitochondrial functions are involved in the pathogenesis of several diseases. Disassembly of the axon's cytoskeleton and the release of neurofilament fragments have been documented during neurodegeneration. However, these changes can also be related to mitochondrial impairments, spanning from reduced mitochondrial quality to altered bioenergetics. Herein, we discuss recent research highlighting some of the pathophysiological roles of cytoskeleton disassembly in aging, neurodegeneration, and neuromuscular diseases, with a focus on studies that explored the relationship between intermediate filaments and mitochondrial signaling as relevant contributors to cellular health and disease.

Keywords:  axonal transport; cell architecture; cell quality; cytoskeleton; mitochondrial quality; muscle aging; neurodegeneration; neurofilaments; sarcomere; vimentin

DOI:  https://doi.org/10.3390/ijms26031100
Nat Aging. 2025 Feb 13.

An mTOR paradox in sarcopenia via BCAA catabolism.

Jerome N Feige.

DOI: https://doi.org/10.1038/s43587-025-00815-3
J Clin Invest. 2025 Feb 11. pii: e186416. [Epub ahead of print]

MBNL overexpression rescues cardiac phenotypes in a myotonic dystrophy type 1 heart mouse model.

Rong-Chi Hu, Yi Zhang, Larissa Nitschke, Sara J Johnson, Ayrea E Hurley, William R Lagor, Zheng Xia, Thomas A Cooper.

  Myotonic Dystrophy Type 1 (DM1) is an autosomal dominant disease caused by a CTG repeat expansion in the DMPK gene. The expanded CUG repeat RNA (CUGexp RNA) transcribed from the mutant allele sequesters the muscleblind-like (MBNL) family of RNA-binding proteins, causing their loss of function and disrupting regulated pre-mRNA processing. We used a DM1 heart mouse model that inducibly expresses CUGexp RNA to test the contribution of MBNL loss to DM1 cardiac abnormalities and explore MBNL restoration as a potential therapy. AAV9-mediated overexpression of MBNL1 and/or MBNL2 significantly rescued DM1 cardiac phenotypes including conduction delays, contractile dysfunction, hypertrophy, and mis-regulated alternative splicing and gene expression. While robust, rescue was partial compared to reduced CUGexp RNA and plateaued with increased exogenous MBNL expression. These findings demonstrate that MBNL loss is a major contributor to DM1 cardiac manifestations, and suggest that additional mechanisms play a role, highlighting the complex nature of DM1 pathogenesis.

Keywords:  Arrhythmias; Cardiovascular disease; Genetic diseases; Genetics; Therapeutics

DOI:  https://doi.org/10.1172/JCI186416
Nature. 2025 Feb 12.

Transcriptional adaptation upregulates utrophin in Duchenne muscular dystrophy.

Lara Falcucci, Christopher M Dooley, Douglas Adamoski, Thomas Juan, Justin Martinez, Angelina M Georgieva, Kamel Mamchaoui, Cansu Cirzi, Didier Y R Stainier.

Duchenne muscular dystrophy (DMD) is a muscle-degenerating disease caused by mutations in the DMD gene, which encodes the dystrophin protein1,2. Utrophin (UTRN), the genetic and functional paralogue of DMD, is upregulated in some DMD patients3-5. To further investigate this UTRN upregulation, we first developed an inducible messenger RNA (mRNA) degradation system for DMD by introducing a premature termination codon (PTC) in one of its alternatively spliced exons. Inclusion of the PTC-containing exon triggers DMD mutant mRNA decay and UTRN upregulation. Notably, blocking nonsense-mediated mRNA decay results in the reversal of UTRN upregulation, whereas overexpressing DMD does not. Furthermore, overexpressing DMDPTC minigenes in wild-type cells causes UTRN upregulation, as does a wild-type DMD minigene containing a self-cleaving ribozyme. To place these findings in a therapeutic context, we used splice-switching antisense oligonucleotides (ASOs) to induce the skipping of out-of-frame exons of DMD, aiming to introduce PTCs. We found that these ASOs cause UTRN upregulation. In addition, when using an ASO to restore the DMD reading frame in myotubes derived from a DMDΔE52 patient, an actual DMD treatment, UTRN upregulation was reduced. Altogether, these results indicate that an mRNA decay-based mechanism called transcriptional adaptation6-8 plays a key role in UTRN upregulation in DMDPTC patients, and they highlight an unexplored therapeutic application of ASOs, as well as ribozymes, in inducing genetic compensation via transcriptional adaptation.

DOI: https://doi.org/10.1038/s41586-024-08539-x