bims-moremu 2025-03-16 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–03–16
33 papers selected by
Anna Vainshtein, Craft Science Inc.

The Loss of HJV Aggravates Muscle Atrophy by Promoting the Activation of the TβRII/Smad3 Pathway.
Atrophic C2C12 Myotubes Activate Inflammatory Response of Macrophages In Vitro.
Stem cell therapy: A promising therapeutic approach for skeletal muscle atrophy.
Mitochondrial fatty acid oxidation regulates adult muscle stem cell function through modulating metabolic flux and protein acetylation.
The Regulatory Role of CircAGGF1 in Myogenic Differentiation and Skeletal Muscle Development.
Dual-filament regulation of relaxation in mammalian fast skeletal muscle.
Cellular Senescence in the Regenerative Niche Hampers Skeletal Muscle Repair.
Development and Characterization of a Sf-1 -Flp Mouse Model.
Skeletal muscle atrophy and dysfunction in obesity and type-2 diabetes mellitus: Myocellular mechanisms involved.
Skeletal muscle mitochondrial dysfunction is associated with increased Gdf15 expression and circulating GDF15 levels in aged mice.
The Mitochondria-Targeted Peptide Therapeutic Elamipretide Improves Cardiac and Skeletal Muscle Function During Aging Without Detectable Changes in Tissue Epigenetic or Transcriptomic Age.
Effects of alpha-ketoisocaproate in oxidative stress-induced C2C12 myotubes via inhibition of p38 MAPK and ERK1/2.
Fndc5/irisin mediates the benefits of aerobic exercise intervention on aging-associated sarcopenia in mice.
Type 2 deiodinase promotes fatty adipogenesis in muscle fibroadipogenic progenitors from adult male mice.
Molecular insights into human soleus muscle atrophy development: long-term dry immersion effects on the transcriptomic profile and post-translational signaling.
Site-1 Protease is a negative regulator of sarcolipin promoter activity.
Muscle-specific Keap1 deletion enhances force production but does not prevent inactivity-induced muscle atrophy in mice.
Expansion and pathogenic activation of skeletal muscle-resident macrophages in mdx5cv/Ccr2-/- mice.
Chronic treatment of old mice with AICAR reverses age-related changes in exercise performance and skeletal muscle gene expression.
SH3KBP1 promotes skeletal myofiber formation and functionality through ER/SR architecture integrity.
Muscle transcriptome profiles in elite male ultra-endurance athletes acclimated to a high-carbohydrate versus low-carbohydrate diet.
Activation of endogenous full-length utrophin by MyoAAV-UA as a therapeutic approach for Duchenne muscular dystrophy.
mir-276a Is Required for Muscle Development in Drosophila and Regulates the FGF Receptor Heartless During the Migration of Nascent Myotubes in the Testis.
Modeling statin-induced myopathy with hiPSC-derived myocytes reveals that impaired proteostasis underlies the myotoxicity and is targetable for the prevention.
Phosphorylation-driven regulation of SIRT1 in muscle senescence: Insights from molecular dynamics simulation and experimental validation.
The mitophagy receptor BNIP3L/Nix coordinates nuclear calcium signaling to modulate the muscle phenotype.
YAP/TAZ-mediated nuclear membrane rupture in promoting senescence of skeletal muscle associated with COPD.
Muscle loss in cancer cachexia: what is the basis for nutritional support?
Aerobic exercise improves inflammation and insulin resistance in skeletal muscle by regulating miR-221-3p via JAK/STAT signaling pathway.
An obesogenic FTO allele causes accelerated development, growth and insulin resistance in human skeletal muscle cells.
Mitochondrial damage in muscle specific PolG mutant mice activates the integrated stress response and disrupts the mitochondrial folate cycle.
Serum Proteomic and Metabolomic Signatures of High Versus Low Physical Function in Octogenarians.
MiR-34b Regulates Muscle Growth and Development by Targeting SYISL.

Int J Mol Sci. 2025 Feb 26. pii: 2016. [Epub ahead of print]26(5):

The Loss of HJV Aggravates Muscle Atrophy by Promoting the Activation of the TβRII/Smad3 Pathway.

Lu Wang, Wuchen Tao, Jiajie Jia, Min Yuan, Wenjiong Li, Peng Zhang, Xiaoping Chen.

  Hemojuvelin (HJV) is a membrane-bound protein prominently expressed in the skeletal muscle, heart, and liver. Despite its established function in iron regulation, the specific role of HJV in muscle physiology and pathophysiology is not well understood. In this study, we explored the involvement of HJV in disuse-induced muscle atrophy and uncovered the potential mechanisms. Hindlimb unloading (HU) resulted in soleus muscle atrophy in wild type (WT) mice, accompanied by a significant decrease in HJV protein expression. The muscle-specific deletion of Hjv (MKO) exacerbated myofiber atrophy, which was associated with an increase in the expression of muscle ubiquitin ligases following HU. Furthermore, the expression of transforming growth factor-β type II receptor (TβRII) and the level of phosphorylated Smad3 (p-Smad3) were elevated after HU, and these effects were exacerbated in MKO mice. The knockdown of TβRII in the skeletal muscle of MKO mice mitigated myofiber atrophy and reversed the hyperactivation of the TβRII/Smad3 pathway induced by HU. Our findings demonstrate that the absence of HJV contributes to the activation of the TβRII/Smad3 signaling pathway and, consequently, the onset of myofiber atrophy in response to HU. Given its abundant expression in skeletal muscle, HJV emerges as a potential therapeutic target for muscle atrophy.

Keywords:  Smad3; T?RII; hemojuvelin; hindlimb unloading; muscle atrophy; ubiquitin ligases

DOI:  https://doi.org/10.3390/ijms26052016
Cells. 2025 Feb 20. pii: 317. [Epub ahead of print]14(5):

Atrophic C2C12 Myotubes Activate Inflammatory Response of Macrophages In Vitro.

Cong Wu, Yishan Tong, Jiapeng Huang, Shuo Wang, Haruki Kobori, Ziwei Zhang, Katsuhiko Suzuki.

   BACKGROUND: Skeletal muscle wasting is commonly observed in aging, immobility, and chronic diseases. In pathological conditions, the impairment of skeletal muscle and immune system often occurs simultaneously. Recent studies have highlighted the initiative role of skeletal muscle in interactions with immune cells. However, the impact of skeletal muscle wasting on macrophage inflammatory responses remains poorly understood.
METHODS: To investigate the effect of atrophic myotubes on the inflammatory response of macrophages, we established two in vitro models to induce myotube atrophy: one induced by D-galactose and the other by starvation. Conditioned medium (CM) from normal and atrophic myotubes were collected and administered to bone marrow-derived macrophages (BMDMs) from mice. Subsequently, lipopolysaccharide (LPS) stimulation was applied, and the expression of inflammatory cytokines was measured via RT-qPCR.
RESULTS: Both D-galactose and starvation treatments reduced myotube diameter and upregulated muscle atrophy-related gene expression. CM from both atrophic myotubes models augmented the gene expression of pro-inflammatory factors in BMDMs following LPS stimulation, including Il6, Il1b, and Nfkb1. Notably, CM from starvation-induced atrophic myotubes also enhanced Il12b, Tnf, and Nos2 expression in BMDMs after stimulation, a response not observed in D-galactose-induced atrophic myotubes.
CONCLUSIONS: These findings suggest that CM from atrophic myotubes enhanced the expression of LPS-induced pro-inflammatory mediators in macrophages.

Keywords:  inflammatory response; macrophage; skeletal muscle wasting

DOI:  https://doi.org/10.3390/cells14050317
World J Stem Cells. 2025 Feb 26. 17(2): 98693

Stem cell therapy: A promising therapeutic approach for skeletal muscle atrophy.

Ying-Jie Wang, Ze-Hao Chen, Yun-Tian Shen, Ke-Xin Wang, Yi-Min Han, Chen Zhang, Xiao-Ming Yang, Bing-Qian Chen.

  Skeletal muscle atrophy results from disruptions in the growth and metabolism of striated muscle, leading to a reduction or loss of muscle fibers. This condition not only significantly impacts patients' quality of life but also imposes substantial socioeconomic burdens. The complex molecular mechanisms driving skeletal muscle atrophy contribute to the absence of effective treatment options. Recent advances in stem cell therapy have positioned it as a promising approach for addressing this condition. This article reviews the molecular mechanisms of muscle atrophy and outlines current therapeutic strategies, focusing on mesenchymal stem cells, induced pluripotent stem cells, and their derivatives. Additionally, the challenges these stem cells face in clinical applications are discussed. A deeper understanding of the regenerative potential of various stem cells could pave the way for breakthroughs in the prevention and treatment of muscle atrophy.

Keywords:  Exosome; Induced pluripotent stem cells; Mesenchymal stem cells; Muscle atrophy; Stem cell; Therapy

DOI:  https://doi.org/10.4252/wjsc.v17.i2.98693
EMBO J. 2025 Mar 10.

Mitochondrial fatty acid oxidation regulates adult muscle stem cell function through modulating metabolic flux and protein acetylation.

Feng Yue, Lijie Gu, Jiamin Qiu, Stephanie N Oprescu, Linda M Beckett, Jessica M Ellis, Shawn S Donkin, Shihuan Kuang.

  During homeostasis and regeneration, satellite cells, the resident stem cells of skeletal muscle, have distinct metabolic requirements for fate transitions between quiescence, proliferation and differentiation. However, the contribution of distinct energy sources to satellite cell metabolism and function remains largely unexplored. Here, we uncover a role of mitochondrial fatty acid oxidation (FAO) in satellite cell integrity and function. Single-cell RNA sequencing revealed progressive enrichment of mitochondrial FAO and downstream pathways during activation, proliferation and myogenic commitment of satellite cells. Deletion of Carnitine palmitoyltransferase 2 (Cpt2), the rate-limiting enzyme in FAO, hampered muscle stem cell expansion and differentiation upon acute muscle injury, markedly delaying regeneration. Cpt2 deficiency reduces acetyl-CoA levels in satellite cells, impeding the metabolic flux and acetylation of selective proteins including Pax7, the central transcriptional regulator of satellite cells. Notably, acetate supplementation restored cellular metabolic flux and partially rescued the regenerative defects of Cpt2-null satellite cells. These findings highlight an essential role of fatty acid oxidation in controlling satellite cell function and suggest an integration of lipid metabolism and protein acetylation in adult stem cells.

Keywords:  CPT2; Fatty Acid Oxidation; Muscle Regeneration; Muscle Satellite Cell; Protein Acetylation

DOI:  https://doi.org/10.1038/s44318-025-00397-1
Animals (Basel). 2025 Feb 28. pii: 708. [Epub ahead of print]15(5):

The Regulatory Role of CircAGGF1 in Myogenic Differentiation and Skeletal Muscle Development.

Wei Hei, Yuxuan Gong, Wenrun Cai, Ruotong Li, Jiayi Chen, Wanfeng Zhang, Mengting Ji, Meng Li, Yang Yang, Chunbo Cai, Xiaohong Guo, Bugao Li.

  Circular RNA (circRNA) has a significant impact on the maturation of skeletal muscle, although their precise functions within this framework remain largely uncharted. This study presents an investigation of the regulatory effect of circAGGF1 on myogenesis in myoblasts, including the potential molecular mechanisms involved. It is revealed that circAGGF1 facilitates the differentiation of myoblasts into other states while simultaneously enhancing the manifestation of type I muscle fibers. In vivo investigations with mice revealed the promotion of skeletal muscle expansion and maturation by circAGGF1, bolstering its regenerative capacity. Mechanistically, circAGGF1 interacts with miR-199a-3p by acting as a sponge, promoting the subsequent expression of Fgf7. Furthermore, rescue experiments indicated a counteraction of the myogenesis induced by circAGGF1 overexpression by miR-199a-3p. To summarize, this research highlights the role played by circAGGF1 in the development of skeletal muscle, providing a valuable resource for enhancing our understanding of skeletal muscle biology.

Keywords:  C2C12; Fgf7; circAGGF1; miR-199a-3p; muscle fiber type; myogenesis

DOI:  https://doi.org/10.3390/ani15050708
Proc Natl Acad Sci U S A. 2025 Mar 18. 122(11): e2416324122

Dual-filament regulation of relaxation in mammalian fast skeletal muscle.

Cameron Hill, Michaeljohn Kalakoutis, Alice Arcidiacono, Flair Paradine Cullup, Yanhong Wang, Atsuki Fukutani, Theyencheri Narayanan, Elisabetta Brunello, Luca Fusi, Malcolm Irving.

  Muscle contraction is driven by myosin motors from the thick filaments pulling on the actin-containing thin filaments of the sarcomere, and it is regulated by structural changes in both filaments. Thin filaments are activated by an increase in intracellular calcium concentration [Ca2+]i and by myosin binding to actin. Thick filaments are activated by direct sensing of the filament load. However, these mechanisms cannot explain muscle relaxation when [Ca2+]i decreases at high load and myosin motors are attached to actin. There is, therefore, a fundamental gap in our understanding of muscle relaxation, despite its importance for muscle function in vivo, for example, for rapid eye movements or, on slower timescales, for the efficient control of posture. Here, we used time-resolved small-angle X-ray diffraction (SAXD) to determine how muscle thin and thick filaments switch OFF in extensor digitorum longus (EDL) muscles of the mouse in response to decreases in either [Ca2+]i or muscle load and to describe the distribution of muscle sarcomere lengths (SLs) during relaxation. We show that reducing load at high [Ca2+]i is more effective in switching OFF both the thick and thin filaments than reducing [Ca2+]i at high load in normal relaxation. In the latter case, the thick filaments initially remain fully ON, although the number of myosin motors bound to actin decreases and the force per attached motor increases. That initial slow phase of relaxation is abruptly terminated by yielding of one population of sarcomeres, triggering a redistribution of SLs that leads to the rapid completion of mechanical relaxation.

Keywords:  actin; mammalian skeletal muscle; myosin; small-angle X-ray diffraction; tropomyosin

DOI:  https://doi.org/10.1073/pnas.2416324122
Aging Dis. 2025 Mar 06.

Cellular Senescence in the Regenerative Niche Hampers Skeletal Muscle Repair.

MingYu Qiu, YangYang Li, QiSen Wang, XiaoTing Jian, JingWen Huang, WeiChao Gui, Jijie Hu, Hua Liao.

With the growing interest in skeletal muscle diseases, understanding the processes, factors, and treatments associated with muscle regeneration is crucial. Skeletal muscle regeneration is a complex process that largely depends on the niche composed of cell populations, such as satellite cells, and their microenvironment. Cellular senescence is associated with various physiological processes and age-related diseases and plays a significant role in the muscle regeneration niche. Deciphering senescence-associated alterations within this niche provides critical insights for developing targeted anti-aging therapies. This review synthesizes recent studies to elucidate the composition of the niche and its cell-cell interactions and outlines the effects of aging on muscle regeneration and corresponding therapeutic strategies. This review summarizes emerging findings and technologies in muscle regeneration, analyzing therapeutic potential and limitations of current approaches for age-related conditions to support research advancement.

DOI: https://doi.org/10.14336/AD.2024.1501
bioRxiv. 2025 Feb 25. pii: 2025.02.21.639566. [Epub ahead of print]

Development and Characterization of a Sf-1 -Flp Mouse Model.

Marco Galvan, Mina Fujitani, Samuel R Heaselgrave, Shreya Thomas, Bandy Chen, Jenny J Lee, Steven C Wyler, Joel K Elmquist, Teppei Fujikawa.

The use of genetically engineered tools, including combinations of Cre-LoxP and Flp-FRT systems, enable the interrogation of complex biology. Steroidogenic factor-1 (SF-1) is expressed in the ventromedial hypothalamic nucleus (VMH). Development of genetic tools, such as mice expressing Flp recombinase (Flp) in SF-1 neurons ( Sf-1 -Flp), will be useful for future studies that unravel the complex physiology regulated by the VMH. Here, we developed and characterized Sf-1 -Flp mice and demonstrated its utility. Flp sequence was inserted into Sf-1 locus with P2A. This insertion did not affect Sf-1 mRNA expression levels and Sf-1 -Flp mice do not have any visible phenotypes. They are fertile and metabolically comparable to wild-type littermate mice. Optogenetic stimulation using adeno-associated virus (AAV)-bearing Flp-dependent channelrhodopsin-2 (ChR2) increased blood glucose and skeletal muscle PGC-1α in Sf-1 -Flp mice. This was similar to SF-1 neuronal activation using Sf-1 -BAC-Cre and AAV-bearing Cre-dependent ChR2. Finally, we generated Sf-1 -Flp mice that lack β2-adrenergic receptors ( Adrβ2 ) only in skeletal muscle with a combination of Cre/LoxP technology ( Sf-1 -Flp::SKM ΔAdrβ2 ). Optogenetic stimulation of SF-1 neurons failed to increase skeletal muscle PGC-1α in Sf-1 -Flp::SKM ΔAdrβ2 mice, suggesting that Adrβ2 in skeletal muscle is required for augmented skeletal muscle PGC-1α by SF-1 neuronal activation. Our data demonstrate that Sf-1 -Flp mice are useful for interrogating complex physiology.

DOI: https://doi.org/10.1101/2025.02.21.639566
Rev Endocr Metab Disord. 2025 Mar 10.

Skeletal muscle atrophy and dysfunction in obesity and type-2 diabetes mellitus: Myocellular mechanisms involved.

Íñigo M Pérez Castillo, Josep M Argilés, Ricardo Rueda, María Ramírez, José M López Pedrosa.

  Obesity and type-2 diabetes mellitus (T2DM) are interrelated metabolic disorders primarily driven by overnutrition and physical inactivity, which oftentimes entails a transition from obesity to T2DM. Compromised musculoskeletal health consistently emerges as a common hallmark in the progression of these metabolic disorders. Skeletal muscle atrophy and dysfunction can further impair whole-body metabolism and reduce physical exercise capacity, thus instigating a vicious cycle that further deteriorates the underlying conditions. However, the myocellular repercussions of these metabolic disturbances remain to be completely clarified. Insulin signaling not only facilitates skeletal muscle glucose uptake but also plays a central role in skeletal muscle anabolism mainly due to suppression of catabolic pathways and facilitating an anabolic response to nutrient feeding. Chronic overnutrition may trigger different myocellular mechanisms proposed to contribute to insulin resistance and aggravate skeletal muscle atrophy and dysfunction. These mechanisms mainly include the inactivation of insulin signaling components through sustained activation of stress-related pathways, mitochondrial dysfunction, a shift to glycolytic skeletal muscle fibers, and hyperglycemia. In the present review, we aim to delve on these mechanisms, providing an overview of the myocellular processes involved in skeletal muscle atrophy and dysfunction under chronic overnutrition, and their contribution to the progression to T2DM.

Keywords:  Atrophy; Dysfunction; Mechanisms; Obesity; Skeletal muscle; Type 2 diabetes mellitus

DOI:  https://doi.org/10.1007/s11154-025-09954-9
Sci Rep. 2025 Mar 08. 15(1): 8101

Skeletal muscle mitochondrial dysfunction is associated with increased Gdf15 expression and circulating GDF15 levels in aged mice.

J Chen, J Kastroll, F M Bello, M M Pangburn, A Murali, P M Smith, K Rychcik, K E Loughridge, A M Vandevender, N Dedousis, I J Sipula, J K Alder, M J Jurczak.

  Growth differentiation factor-15 (GDF15) is a biomarker of multiple disease states and circulating GDF15 levels are increased during aging in both pre-clinical animal models and human studies. Accordingly, multiple stressors have been identified, including mitochondrial dysfunction, that lead to induction of Gdf15 expression downstream of the integrated stress response (ISR). For some disease states, the source of increased circulating GDF15 is evident based on the specific pathology. Aging, however, presents a less tractable system for understanding the source of increased plasma GDF15 levels in that cellular dysfunction with aging can be pleiotropic and heterogeneous. To better understand which organ or organs contribute to increased circulating GDF15 levels with age, and whether changes in metabolic and mitochondrial dysfunction were associated with these potential changes, we compared young 12-week-old and middle-aged 52-week-old C57BL/6 J mice using a series of metabolic phenotyping studies and by comparing circulating levels of GDF15 and tissue-specific patterns of Gdf15 expression. Overall, we found that Gdf15 expression was increased in skeletal muscle but not liver, white or brown adipose tissue, kidney or heart of middle-aged mice, and that insulin sensitivity and mitochondrial respiratory capacity were impaired in middle-aged mice. These data suggest that early changes in skeletal muscle mitochondrial function and metabolism contribute to increased circulating GDF15 levels observed during aging.

Keywords:  Aging; Energy expenditure; Insulin resistance; Integrated stress response; Respirometry

DOI:  https://doi.org/10.1038/s41598-025-92572-x
Aging Cell. 2025 Mar 13. e70026

The Mitochondria-Targeted Peptide Therapeutic Elamipretide Improves Cardiac and Skeletal Muscle Function During Aging Without Detectable Changes in Tissue Epigenetic or Transcriptomic Age.

Wayne Mitchell, Gavin Pharaoh, Alexander Tyshkovskiy, Matthew Campbell, David J Marcinek, Vadim N Gladyshev.

  Aging-related decreases in cardiac and skeletal muscle function are strongly associated with various comorbidities. Elamipretide (ELAM), a novel mitochondria-targeted peptide, has demonstrated broad therapeutic efficacy in ameliorating disease conditions associated with mitochondrial dysfunction across both clinical and pre-clinical models. Herein, we investigated the impact of 8-week ELAM treatment on pre- and post-measures of C57BL/6J mice frailty, skeletal muscle, and cardiac muscle function, coupled with post-treatment assessments of biological age and affected molecular pathways. We found that health status, as measured by frailty index, cardiac strain, diastolic function, and skeletal muscle force, is significantly diminished with age, with skeletal muscle force changing in a sex-dependent manner. Conversely, ELAM mitigated frailty accumulation and was able to partially reverse these declines, as evidenced by treatment-induced increases in cardiac strain and muscle fatigue resistance. Despite these improvements, we did not detect statistically significant changes in gene expression or DNA methylation profiles indicative of molecular reorganization or reduced biological age in most ELAM-treated groups. However, pathway analyses revealed that ELAM treatment showed pro-longevity shifts in gene expression, such as upregulation of genes involved in fatty acid metabolism, mitochondrial translation, and oxidative phosphorylation, and downregulation of inflammation. Together, these results indicate that ELAM treatment is effective at mitigating signs of sarcopenia and cardiac dysfunction in an aging mouse model, but that these functional improvements occur independently of detectable changes in epigenetic and transcriptomic age. Thus, some age-related changes in function may be uncoupled from changes in molecular biological age.

Keywords:  aging; aging biomarkers; cardiac dysfunction; elamipretide; epigenetic clocks; mitochondria; transcriptomic clocks

DOI:  https://doi.org/10.1111/acel.70026
Biochem Biophys Rep. 2025 Mar;41 101955

Effects of alpha-ketoisocaproate in oxidative stress-induced C2C12 myotubes via inhibition of p38 MAPK and ERK1/2.

Pooreum Lim, Sang Woo Woo, Jihye Han, Young Lim Lee, Jae Ho Shim, Hyeon Soo Kim.

  Sarcopenia is an age-related muscle atrophy characterized by decreased muscle mass and function. However, potential treatments to alleviate sarcopenia remain limited. In this study, we investigated the effects of α-ketoisocaproate (KIC) on C2C12 differentiation and reactive oxygen species (ROS)-induced atrophy in C2C12 myotubes. We demonstrated that KIC upregulates the expression of myogenic differentiation factors, including myoblast determination protein 1 (MyoD) and myogenin (MyoG), during C2C12 differentiation. Additionally, KIC enhanced the expression of myosin heavy chain (MHC) isoforms MHC1, MHC2b, and MHC2x in C2C12 myotubes. KIC suppressed the decreased MyoG expression and the increase in the muscle atrophy-related factor, muscle atrophy F-box (MAFbx), in ROS-induced C2C12 myotubes. In addition, it restored the reduced expression of MHC and the diameter of C2C12 myotubes. We showed that KIC alleviated muscle atrophy by inhibiting mitogen-activated protein kinase (MAPK) signaling pathways, such as p38 MAPK and extracellular signal-regulated kinase 1/2 (ERK1/2). These findings suggest that KIC may serve as a potential therapeutic agent for ameliorating sarcopenia by inhibiting MAPK signaling in ROS-induced skeletal muscle cells.

Keywords:  C2C12; ERK1/2; Muscle atrophy; ROS; Sarcopenia; p38 MAPK; α-ketoisocaproate

DOI:  https://doi.org/10.1016/j.bbrep.2025.101955
Eur Geriatr Med. 2025 Mar 13.

Fndc5/irisin mediates the benefits of aerobic exercise intervention on aging-associated sarcopenia in mice.

Yuxia Ma, Yi Liu, Jiachuang Zheng, Zhixia Zheng, Jingjing Li.

   METHODS: In this study, 24-month-old (aged) mice were used as a naturally occurring model of aging-associated sarcopenia, while 2-month-old (young) mice served as the normal control. Six weeks of treadmill training was employed as an aerobic exercise intervention. The mRNA and protein levels of fibronectin type III domain-containing protein 5 (Fndc5/irisin), MuRF1, and Atrogin-1 in gastrocnemius muscles were analyzed using qRT-PCR and Western blot. Oxidative stress was assessed using relevant detection kits. Skeletal muscle function was evaluated through the four-paw hanging test, rotarod test, grip strength assay, and measurements of quadriceps, tibialis anterior, and gastrocnemius muscle mass.
RESULTS: Aerobic exercise interventions enhanced skeletal muscle function by increasing hanging time, maximum speed, grip strength, and increased quadriceps, gastrocnemius, and tibialis anterior muscle mass. On the other hand, aerobic exercise reduced MuRF1 and Atrogin-1 expression in the gastrocnemius muscles of sarcopenia mice, along with lower malondialdehyde levels, and higher superoxide dismutase activity, T-ATPase, and glutathione peroxidase activity. A decline in Fndc5/irisin expression was further detected in the gastrocnemius muscles with aging. In Fndc5-knockout aged mice, aerobic exercise failed to improve skeletal muscle function compared to wild-type aged mice, as evaluated by hanging time, grip strength, maximum speed, and quadriceps, gastrocnemius, and tibialis anterior muscle mass, further validating the involvement of Fndc5 in the improvement of aging-associated sarcopenia.
CONCLUSION: Aerobic exercise improves aging-associated sarcopenia in mice, with Fndc5/irisin playing a role in this process.

Keywords:  Aerobic exercise; Age; Fndc5; Irisin; Sarcopenia

DOI:  https://doi.org/10.1007/s41999-025-01181-4
Endocrinology. 2025 Mar 10. pii: bqaf050. [Epub ahead of print]

Type 2 deiodinase promotes fatty adipogenesis in muscle fibroadipogenic progenitors from adult male mice.

Cristina Luongo, Daniela Di Girolamo, Raffaele Ambrosio, Sara Di Cintio, Maria Angela De Stefano, Tommaso Porcelli, Domenico Salvatore.

  Fibro-adipogenic progenitor cells (FAPs) are a heterogeneous population of multipotent mesenchymal cells that give rise to fibroblasts and adipocytes. In response to muscle injury, FAPs are activated and cooperate with inflammatory and muscle stem cells to promote muscle regeneration. In pathological conditions, such as muscular dystrophies, this coordinated response is partially lost and an accumulation of FAPs is observed which is responsible for a maladaptive fibrosis, ectopic fat deposition and impaired muscle regeneration. The role of intracellular thyroid hormone (TH) signaling in this cellular context is largely unknown. Here we show that intracellular T3 concentration in FAPs is increased in vitro during adipogenic differentiation via the increase of the T3-producing type 2 deiodinase (D2). The adipogenic potential is reduced in FAPs cultured in the presence of rT3, a specific D2 inhibitor, while exogenous administration of THs is able to induce the expression of relevant adipogenic genes. Accordingly, upon genetic D2 depletion in vivo, adipogenesis was significantly reduced in D2KO compared to control mice. These data were confirmed using a FAP-inducible specific D2-KO mouse model, suggesting that a cell-specific D2-depletion in FAPs is sufficient to decrease fatty muscle infiltration and to improve muscle regeneration. Taken together, these data show that TH signaling is dynamically modulated in FAPs wherein D2-produced T3 is required to promote maturation of FAPs into adipocytes.

Keywords:  adipogenesis; deiodinase; fibroadipogenic progenitors; thyroid hormone

DOI:  https://doi.org/10.1210/endocr/bqaf050
Physiol Genomics. 2025 Mar 12.

Molecular insights into human soleus muscle atrophy development: long-term dry immersion effects on the transcriptomic profile and post-translational signaling.

Roman O Bokov, Kristina A Sharlo, Natalia A Vilchinskaya, Sergey A Tyganov, Olga V Turtikova, Sergey V Rozhkov, Ruslan M Deviatiiarov, Oleg A Gusev, Elena S Tomilovskaya, Boris S Shenkman, Oleg I Orlov.

  Background: Muscle disuse results in complex signaling alterations followed by structural and functional changes, such as atrophy, force decrease and slow-to-fast fiber-type shift. Little is known about human skeletal muscle signaling alterations under long-term muscle disuse. Methods: In this study, we describe the effects of 21-day dry immersion on human postural soleus muscle. We performed both transcriptomic analysis and Western blots to describe the states of the key signaling pathways regulating soleus muscle fiber size, fiber-type, and metabolism. Results: 21-day dry immersion resulted in both slow-type and fast-type myofibers atrophy, downregulation of rRNA content, and mTOR signaling. 21-day dry immersion also leads to slow-to-fast fiber-type and gene expression shift, upregulation of p-eEF2, p-CaMKII, p-ACC content and downregulation of NFATc1 nuclear content. It also caused massive gene expression alterations associated with calcium signaling, cytoskeletal parameters, and downregulated mitochondrial signaling (including fusion, fission, and marker of mitochondrial density).

Keywords:  Atrophy; Human; Immersion; Muscle; Signaling

DOI:  https://doi.org/10.1152/physiolgenomics.00196.2024
bioRxiv. 2025 Feb 28. pii: 2025.02.25.639963. [Epub ahead of print]

Site-1 Protease is a negative regulator of sarcolipin promoter activity.

Isha Sharma, Meredith O Kelly, Katelyn Hanners, Ella S Shin, Muhammad G Mousa, Shelby Ek, Gretchen A Meyer, Rita T Brookheart.

The timed contraction and relaxation of myofibers in tissues such as the heart and skeletal muscle occurs via the tightly regulated movement of calcium ions into and out of the sarcoplasmic reticulum (SR). In skeletal muscle, this phenomenon enables humans to exercise, perform day-to-day tasks, and to breathe. Sarcolipin, a small regulatory protein, prevents calcium ions from entering the SR by binding to and inhibiting SERCA, contributing to myofiber contraction. Disruptions in sarcolipin expression are implicated in the pathophysiology of obesity and musculoskeletal disease. However, the mechanisms regulating sarcolipin expression are not clearly understood. We recently showed that Site-1 Protease (S1P) is a regulator of skeletal muscle function and mass. Here, we report that deleting S1P in mouse skeletal muscle increases sarcolipin expression, without impacting calcium SR flux. In cultured cells, S1P negatively regulates sarcolipin by activating the transcription factor ATF6, which inhibits basal- and calcineurin-stimulated sarcolipin promoter activity. We identified a cAMP response element binding protein (CREB) binding site on the sarcolipin promoter that is necessary for promoter activation, and show that in muscle, CREB binds to the sarcolipin promoter and that this binding is enhanced when S1P is deleted. These discoveries expand our knowledge of S1P biology and the mechanisms controlling calcium regulatory genes.

DOI: https://doi.org/10.1101/2025.02.25.639963
FASEB J. 2025 Mar 31. 39(6): e70464

Muscle-specific Keap1 deletion enhances force production but does not prevent inactivity-induced muscle atrophy in mice.

Edwin R Miranda, Justin L Shahtout, Shinya Watanabe, Norah Milam, Takuya Karasawa, Subhasmita Rout, Donald L Atkinson, William L Holland, Micah J Drummond, Katsuhiko Funai.

  Immobilization-associated muscle atrophy and weakness appear to be driven in part by oxidative stress. Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) is a critical redox rheostat that regulates oxidative stress responses, and its deletion is known to accelerate muscle atrophy and weakness during aging (sarcopenia) or denervation. Conversely, pharmacologic activation of NRF2 extends mouse lifespan and attenuates sarcopenia. Similarly, deletion of Kelch-like ECH-associated Protein 1 (Keap1), a negative regulator of NRF2, enhances exercise capacity. The purpose of this study was to determine whether muscle-specific Keap1 deletion is sufficient to prevent muscle atrophy and weakness in mice following 7 days of hindlimb unloading (HU). To test this hypothesis, control (Ctrl) and tamoxifen-inducible, muscle-specific Keap1 knockout (mKO) mice were subjected to either normal housing (Sham) or HU for 7 days. Activation of NRF2 in muscle was confirmed by increased mRNA of NRF2 targets thioredoxin 1 (Txn1) and NAD(P)H quinone dehydrogenase 1 (NQO1) in mKO mice. Keap1 deletion had an effect to increase force-generating capacity at baseline. However, muscle masses, cross-sectional area, and ex vivo force were not different between mKO and Ctrl HU mice. In addition, muscle 4-hydroxynonenal-modified proteins and protein carbonyls were unaffected by Keap1 deletion. These data suggest that NRF2 activation improves muscle force production during ambulatory conditions but is not sufficient to prevent muscle atrophy or weakness following 7 days of HU.

Keywords:  NRF2; carbonyl stress; oxidative stress; redox; sarcopenia

DOI:  https://doi.org/10.1096/fj.202402810R
Proc Natl Acad Sci U S A. 2025 Mar 18. 122(11): e2410095122

Expansion and pathogenic activation of skeletal muscle-resident macrophages in mdx5cv/Ccr2-/- mice.

Yinhang Wang, Xingyu Wang, Salam Alabdullatif, Sachiko T Homma, Yuriy O Alekseyev, Lan Zhou.

  Infiltrating macrophages contribute to muscle dystrophic changes in Duchenne muscular dystrophy (DMD). In a DMD mouse model, mdx5cv mice, CC chemokine receptor type 2 (CCR2) deficiency diminishes Ly6Chi macrophage infiltration by blocking blood Ly6Chi inflammatory monocyte recruitment. This is accompanied by transient improvement of muscle damage, fibrosis, and regeneration. The benefit, however, is lost after the expansion of intramuscular Ly6Clo macrophages. To address the mechanisms underlying the Ly6Clo macrophage expansion, we compared mdx5cv/Nur77-/- and mdx5cv/Ccr2-/-/Nur7-/- mice with mdx5cv and mdx5cv/Ccr2-/- mice, respectively, and found no evidence to suggest Ly6Clo monocyte recruitment by dystrophic muscles. Single-cell RNA sequencing analysis and Flt3cre/Rosa26LSL-YFP-based lineage tracing of macrophage origins demonstrated the expansion and pathogenic activation of muscle resident macrophages in CCR2-deficient mdx5cv mice. The expansion was associated with increased cell proliferation, which appeared induced by colony-stimulating factor-1 (CSF-1) derived from fibro/adipogenic progenitors (FAPs). Our study establishes a pathogenic role for skeletal muscle resident macrophages and supports a regulatory role of FAPs in stimulating the expansion of resident macrophages in the DMD mouse model when the inflammatory macrophage infiltration is inhibited.

Keywords:  CSF-1; FAPs; inflammation; macrophage; muscular dystrophy

DOI:  https://doi.org/10.1073/pnas.2410095122
FASEB Bioadv. 2025 Mar;7(3): e1491

Chronic treatment of old mice with AICAR reverses age-related changes in exercise performance and skeletal muscle gene expression.

Shalene H Wilcox, Jouber Calixto, Steven D Dray, Daniel M Rasch, Andrew H Smith, Kole D Brodowski, Jonathon T Hill, David M Thomson.

  Sarcopenia refers to the decline in muscle mass and function that occurs with advancing age. It is driven by alterations in multiple cellular processes. AMP-activated protein kinase (AMPK) is a cellular energy sensor that opposes many age-related changes, making it an attractive target for the treatment of sarcopenia. This study aimed to test the effect of chronic treatment of old mice with the AMPK-activating prodrug, AICAR, on treadmill running capacity and muscle mass, force production, gene expression, and intracellular markers relevant to sarcopenia. Old (23 months) mice were tested for treadmill running capacity, then randomly assigned to receive daily treatment with AICAR (OA; 300 to 500 mg/kg, delivered via subcutaneous injection) or an equivalent volume of saline vehicle (OS) for 31 days. Young (5 months) saline-treated mice (YS) served as controls. Treadmill posttesting was performed after 24 days, and the mice were euthanized after 31 days of treatment. Extensor digitorum longus (EDL) muscles were tested for force generation and RNA sequencing, RT-PCR, and western blotting were performed on quadricep muscles. Treadmill running capacity declined from pre- to posttesting by 24.5% in OS mice. This decline was not observed in YS or OA mice. Quadricep weight was ~8% higher, and tetanic force production by the EDL muscle increased by 26.4% in OA versus OS. These phenotypic improvements with AICAR treatment were accompanied by changes in gene expression in OA/YS versus OS muscles consistent with the "rejuvenation" of gene ontologies associated with connective tissue, neurodegenerative disease, Akt signaling, and mitochondrial function, among others. AICAR increased the mitochondrial markers cytochrome C by ~33%, and citrate synthase by ~22%. Serum insulin-like growth factor-1 levels increased, and Akt phosphorylation tended (p = 0.07) to increase with AICAR treatment. Although protein levels of the mTORC1 signaling pathway intermediate, rpS6, were higher in OA versus OS muscles, the phosphorylation of mTORC1 pathway intermediates was unaffected. On the other hand, gene expression of the muscle-specific ubiquitin ligases Mafbx and Murf1 were reduced with AICAR treatment. AICAR treatment mildly increased/preserved muscle mass and force production and prevented a decline in treadmill running performance in old mice. These effects were associated with altered skeletal muscle gene and protein expression, suggesting improved mitochondrial content and metabolic signaling (particularly through Akt) as contributing factors to the observed phenotypic effects. Our findings support further development of AMPK-activating drugs as a therapeutic strategy for improving age-related organismal dysfunction and sarcopenia.

Keywords:  AMPK; exercise; mTORC1; mitochondria; sarcopenia

DOI:  https://doi.org/10.1096/fba.2024-00252
EMBO Rep. 2025 Mar 10.

SH3KBP1 promotes skeletal myofiber formation and functionality through ER/SR architecture integrity.

Alexandre Guiraud, Nathalie Couturier, Emilie Christin, Léa Castellano, Marine Daura, Carole Kretz-Remy, Alexandre Janin, Alireza Ghasemizadeh, Peggy Del Carmine, Laloe Monteiro, Ludivine Rotard, Colline Sanchez, Vincent Jacquemond, Claire Burny, Stéphane Janczarski, Anne-Cécile Durieux, David Arnould, Norma Beatriz Romero, Mai Thao Bui, Vladimir L Buchman, Laura Julien, Marc Bitoun, Vincent Gache.

  Dynamic changes in the arrangement of myonuclei and the organization of the sarcoplasmic reticulum are important determinants of myofiber formation and muscle function. To find factors associated with muscle integrity, we perform an siRNA screen and identify SH3KBP1 as a new factor controlling myoblast fusion, myonuclear positioning, and myotube elongation. We find that the N-terminus of SH3KBP1 binds to dynamin-2 while the C-terminus associates with the endoplasmic reticulum through calnexin, which in turn control myonuclei dynamics and ER integrity, respectively. Additionally, in mature muscle fibers, SH3KBP1 contributes to the formation of triads and modulates the Excitation-Contraction Coupling process efficiency. In Dnm2R465W/+ mice, a model for centronuclear myopathy (CNM), depletion of Sh3kbp1 expression aggravates CNM-related atrophic phenotypes and impaired autophagic flux in mutant skeletal muscle fiber. Altogether, our results identify SH3KBP1 as a new regulator of myofiber integrity and function.

Keywords:  Centronuclear Myopathies; Endoplasmic Reticulum; Myonuclear Positioning; Triads

DOI:  https://doi.org/10.1038/s44319-025-00413-9
Sci Rep. 2025 Mar 11. 15(1): 8419

Muscle transcriptome profiles in elite male ultra-endurance athletes acclimated to a high-carbohydrate versus low-carbohydrate diet.

Catherine Saenz, Kaleen M Lavin, Elaine C Lee, Carl M Maresh, William J Kraemer, Marcas M Bamman, Timothy J Broderick, Jeff S Volek.

Low-carbohydrate, high-fat diets enhance lipid metabolism and decrease reliance on glucose oxidation in athletes, but the associated gene expression patterns remain unclear. The purpose of this study was to determine whether coordinated molecular pathways in skeletal muscle may be revealed by differential expression of genes driven by dietary profile, exercise, and/or their interaction. We investigated the skeletal muscle transcriptome in elite ultra-endurance athletes habitually (~ 20 months) consuming a high-carbohydrate, low-fat (HC, n = 10, 33 ± 6y, VO2max = 63.4 ± 6.2 mL O2•kg-1•min-1) or low-carbohydrate, high-fat (LC, n = 10, 34 ± 7y, VO2max = 64.7 ± 3.7 mL O2•kg-1•min-1) diet. Skeletal muscle gene expression was measured at baseline (BL), immediately-post (H0), and 2 h (H2) after 3 h submaximal treadmill running. Diet induced a coordinated but divergent expression pattern at BL where LC had higher expression of genes associated with lipid metabolism. Exercise resulted in a dynamic but uniform gene response, with no major differences between groups (H0). At H2, gene expression patterns were associated with differential pathway activity, including inflammation/immunity, suggesting a diet-specific influence on early muscle recovery. These results indicate that low-carbohydrate, high-fat diets lead to differences in resting and exercise-induced skeletal muscle gene expression patterns, underlying our previous findings of differential fuel utilization in elite ultra-endurance athletes.

DOI: https://doi.org/10.1038/s41598-025-88963-9
Nat Commun. 2025 Mar 10. 16(1): 2398

Activation of endogenous full-length utrophin by MyoAAV-UA as a therapeutic approach for Duchenne muscular dystrophy.

Ruo Wu, Peng Li, Puhao Xiao, Shu Zhang, Xiaopeng Wang, Jie Liu, Wenjie Sun, Yue Chang, Xiuyi Ai, Lijiao Chen, Yan Zhuo, Jiaojian Wang, Zhengbo Wang, Shangang Li, Yuanyuan Li, Weizhi Ji, Wenting Guo, Shiwen Wu, Yongchang Chen.

Activation of endogenous full-length utrophin, a dystrophin homolog, presents an attractive therapeutic strategy for Duchenne muscular dystrophy (DMD), regardless of mutation types and loci. However, current dCas9-based activators are too large for efficient adeno-associated virus delivery, and the feasibility and durability of such treatments remain unclear. Here, we develop a muscle-targeted utrophin activation system using the compact dCasMINI-VPR system, termed MyoAAV-UA. Systemic administration of MyoAAV-UA in male mdx mice leads to substantial upregulation of utrophin at the sarcolemma, resulting in significant improvements in skeletal muscle function and a slowing of heart function deterioration. These benefits remain observable at six months post-treatment. In male nonhuman primates, systemic administration of MyoAAV-UA increases utrophin expression by twofold in skeletal muscle, with no significant side effects observed. Furthermore, MyoAAV-UA upregulates utrophin and utrophin-glycoprotein complexes in induced pluripotent stem cell-derived myotubes from DMD patients. In conclusion, these findings demonstrate the potential of MyoAAV-UA as a therapeutic approach for DMD.

DOI: https://doi.org/10.1038/s41467-025-57831-5
Cells. 2025 Mar 03. pii: 368. [Epub ahead of print]14(5):

mir-276a Is Required for Muscle Development in Drosophila and Regulates the FGF Receptor Heartless During the Migration of Nascent Myotubes in the Testis.

Mathieu Preußner, Maik Bischoff, Susanne Filiz Önel.

  MicroRNAs function as post-transcriptional regulators in gene expression and control a broad range of biological processes in metazoans. The formation of multinucleated muscles is essential for locomotion, growth, and muscle repair. microRNAs have also emerged as important regulators for muscle development and function. In order to identify new microRNAs required for muscle formation, we have performed a large microRNA overexpression screen. We screened for defects during embryonic and adult muscle formation. Here, we describe the identification of mir-276a as a regulator for muscle migration during testis formation. The mir-276a overexpression phenotype in testis muscles resembles the loss-of-function phenotype of heartless. A GFP sensor assay reveals that the 3'UTR of heartless is a target of mir-276a. Furthermore, we found that mir-276a is essential for the proper development of indirect flight muscles and describe a method for determining the number of nuclei for each of the six longitudinal muscle fibers (DLMs), which are part of the indirect flight muscles.

Keywords:  DLM; IFM; indirect flight muscles; larval body wall muscles; microRNAs; myoblast fusion; testis muscle

DOI:  https://doi.org/10.3390/cells14050368
Am J Physiol Cell Physiol. 2025 Mar 07.

Modeling statin-induced myopathy with hiPSC-derived myocytes reveals that impaired proteostasis underlies the myotoxicity and is targetable for the prevention.

Xiaolin Zhao, Liyang Ni, Miharu Kubo, Mariko Matsuto, Hidetoshi Sakurai, Makoto Shimizu, Yu Takahashi, Ryuichiro Sato, Yoshio Yamauchi.

  Statins, HMG-CoA reductase inhibitors, have been widely prescribed to lower circulating low-density lipoprotein cholesterol levels and reduce the risk of cardiovascular disease. Although statins are well tolerated, statin-associated muscle symptoms (SAMS) are the major adverse effect and cause statin intolerance. Therefore, understanding the molecular mechanisms of SAMS and developing effective strategies for its prevention are of significant clinical importance; however, both remain unclear. Here we establish a model of statin-induced myopathy (SIM) with human induced pluripotent stem cell (hiPSC)- derived myocytes (iPSC-MCs) and investigate the effect of statins on protein homeostasis (proteostasis) that affects skeletal muscle wasting and myotoxicity. We show that treating hiPSC-MCs with statins induces atrophic phenotype and myotoxicity, establishing an hiPSC-based SIM model. We then examine whether statins impair the balance between protein synthesis and degradation. The results show that statins not only suppress protein synthesis but also promote protein degradation by upregulating the expression of the muscle-specific E3 ubiquitin ligase Atrogin-1 in a mevalonate pathway-dependent manner. Mechanistically, blocking the mevalonate pathway inactivates the protein kinase Akt, leading to the inhibition of mTORC1 but the activation of GSK3β and FOXO1. These changes explain the statin-induced impairment in proteostasis. Finally, we show that pharmacological blockage of FOXO1 prevents SIM in hiPSC-MCs, implicating FOXO1 as a key mediator of SIM. Taken together, this study suggests that the mevalonate pathway is critical for maintaining skeletal muscle proteostasis and identifies FOXO1 as a potential target for preventing SIM.

Keywords:  Human induced pluripotent stem cell (hiPSC); proteostasis; skeletal muscle; statin; statin-associated muscle symptoms (SAMS)

DOI:  https://doi.org/10.1152/ajpcell.00714.2024
Int J Biol Macromol. 2025 Mar 06. pii: S0141-8130(25)02285-8. [Epub ahead of print]306(Pt 4): 141734

Phosphorylation-driven regulation of SIRT1 in muscle senescence: Insights from molecular dynamics simulation and experimental validation.

Siyao Liu, Liang Shan, Yue Li, Jinbao Xiang, Hansi Zhang.

  Sirtuin 1 (SIRT1) is a key regulator of mitochondrial function and inflammatory responses, both of which are critical in the progression of muscle aging and sarcopenia. While SIRT1's activity is known to be regulated by post-translational modifications, the specific role of Ser46 phosphorylation has not been fully elucidated. In this study, we explored the effects of Ser46 phosphorylation on SIRT1's structural stability, subcellular localization, and downstream signaling in the context of muscle cell senescence. Using a combination of molecular dynamics (MD) simulations and in vitro assays with C2C12 myoblasts, we demonstrated that phosphorylation at Ser46 enhances SIRT1's structural stability by reducing flexibility in its nuclear localization signal (NLS) and catalytic domains. This modification promotes nuclear translocation of SIRT1 and is associated with a reduction in PGC-1α expression and mitochondrial membrane potential. Additionally, Ser46 phosphorylation activates NF-κB-mediated inflammatory pathways and is associated with increased p53 expression and SA-β-gal activity, hallmarks of cellular senescence. JC-1 staining further revealed that Ser46 phosphorylation compromises mitochondrial membrane potential. These findings reveal a previously unrecognized mechanism by which Ser46 phosphorylation shifts SIRT1's function toward promoting inflammation and muscle senescence, providing a potential target for therapeutic interventions in age-related muscle degeneration.

Keywords:  Nuclear localization; Phosphorylation; SIRT1; Sarcopenia

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.141734
Autophagy. 2025 Mar 10.

The mitophagy receptor BNIP3L/Nix coordinates nuclear calcium signaling to modulate the muscle phenotype.

Jared T Field, Donald Chapman, Yan Hai, Saeid Ghavami, Adrian R West, Berkay Ozerklig, Ayesha Saleem, Julia Kline, Asher A Mendelson, Jason Kindrachuk, Barbara Triggs-Raine, Joseph W Gordon.

  Mitochondrial quality control is critical in muscle to ensure contractile and metabolic function. BNIP3L/Nix is a BCL2 member, a mitophagy receptor, and has been implicated in muscle atrophy. Human genome-wide association studies (GWAS) suggest altered BNIP3L expression could predispose to mitochondrial disease. To investigate BNIP3L function, we generated a muscle-specific knockout model. bnip3l knockout mice displayed a ragged-red fiber phenotype, along with accumulation of mitochondria and endo/sarcoplasmic reticulum with altered morphology. Intriguingly, bnip3l knockout mice were more insulin sensitive with a corresponding increase in glycogen-rich muscle fibers. Kinome and gene expression analyses revealed that bnip3l knockout impairs NFAT and MSTN (myostatin) signaling, with alterations in muscle fiber-type and evidence of regeneration. Mechanistic experiments demonstrated that BNIP3L modulates mitophagy, along with reticulophagy leading to altered nuclear calcium signaling. Collectively, these observations identify novel roles for BNIP3L coordinating selective autophagy, oxidative gene expression, and signaling pathways that maintain the muscle phenotype.

Keywords:  BNIP3L/Nix; calcium signaling; mitophagy; muscle; myostatin

DOI:  https://doi.org/10.1080/15548627.2025.2476872
Respir Res. 2025 Mar 12. 26(1): 98

YAP/TAZ-mediated nuclear membrane rupture in promoting senescence of skeletal muscle associated with COPD.

Ge Gong, Shuping Shen, Shaoran Shen, Ran Wang, Tianping Zheng, Wei Xu, Jianqing Wu.

  Patients with chronic obstructive pulmonary disease (COPD) often develop complications associated with sarcopenia; however, the underlying mechanisms remain unclear. Through a combination of in vitro and in vivo experiments, as well as bioinformatics analysis, our study identified YAP/TAZ as a key regulator of the aging phenotype in the skeletal muscle of COPD patients. In skeletal muscle affected by cigarette smoke-induced COPD, we observed significant reductions in YAP/TAZ levels, alongside markers indicative of skeletal muscle aging and dysfunction. Notably, overexpression of YAP/TAZ significantly improved these conditions. Our results suggest a novel mechanism whereby the maintenance of YAP/TAZ activity interacts with ACTR2 to preserve nuclear membrane integrity and reduce cytoplasmic dsDNA levels, thereby attenuating STING activation and cellular senescence. Additionally, we found that YAP is involved in the transcriptional regulation of the ACTR2 promoter region. Overall, preserving YAP/TAZ activity may help prevent skeletal muscle aging associated with COPD, representing a new strategy for intervening in COPD-related sarcopenia.

Keywords:  ACTR2; COPD; Nuclear membrane rupture; Sarcopenia; Senescence; YAP/TAZ

DOI:  https://doi.org/10.1186/s12931-025-03170-4
Front Pharmacol. 2025 ;16 1519278

Muscle loss in cancer cachexia: what is the basis for nutritional support?

Jaline Faiad, Márcia Fábia Andrade, Gabriela de Castro, Joyce de Resende, Marina Coêlho, Giovana Aquino, Marilia Seelaender.

  Cancer cachexia (CC) is characterized by significant skeletal muscle wasting, and contributes to diminished quality of life, while being associated with poorer response to treatment and with reduced survival. Chronic inflammation plays a central role in driving CC progression, within a complex interplay favoring catabolism. Although cachexia cannot be fully reversed by conventional nutritional support, nutritional intervention shows promise for the prevention and treatment of the syndrome. Of special interest are nutrients with antioxidant and anti-inflammatory potential and those that activate pathways involved in muscle mass synthesis and/or in the inhibition of muscle wasting. Extensive research has been carried out on novel nutritional supplements' power to mitigate CC impact, while the mechanisms through which some nutrients or bioactive compounds exert beneficial effects on muscle mass are still not totally clear. Here, we discuss the most studied supplements and nutritional strategies for dealing with muscle loss in CC.

Keywords:  cancer cachexia; chronic inflammation; muscle wasting; nutritional supplementation; protein synthesis

DOI:  https://doi.org/10.3389/fphar.2025.1519278
Front Physiol. 2025 ;16 1534911

Aerobic exercise improves inflammation and insulin resistance in skeletal muscle by regulating miR-221-3p via JAK/STAT signaling pathway.

Nan Li, Liang Zhang, Qiaofeng Guo, Haiyan Shi, Yanming Gan, Weiqing Wang, Xiaoying Yang, Yue Zhou.

   Background: Exercise improves insulin sensitivity and lipid metabolism while the mechanisms remain unclear. MicroRNAs (miRNAs) have been linked to the development of type 2 diabetes mellitus (T2DM) and served as a potential therapeutic target. The study aimed to explore how aerobic exercise prevents chronic inflammation and insulin resistance (IR) in skeletal muscle.
Methods: Fifty C57BL/6J male mice were divided into a normal (CON) or high-fat diet (HFD) for 12 weeks, followed by treadmill training for 8 weeks. Glucose levels were evaluated by glucose tolerance test, insulin tolerance test and kits. Chronic inflammatory states were evaluated by enzyme-linked immunosorbent assay and immunofluorescence stain. The role of miR-221-3p was determined using miRNA sequencing and dual luciferase reporter gene assays. Metabolic alterations in skeletal muscle were investigated by Real-time PCR and Western blot.
Results: Aerobic exercise reduced body weight, fasting blood glucose gain, and improved insulin sensitivity. It suppressed inflammation by altering IL-1β, IL-10 levels, and macrophage polarization in the skeletal muscle. Moreover, exercise prevented chronic inflammation by diminished miR-221-3p and downstream JAK/STAT pathways.
Conclusion: Aerobic exercise improved chronic inflammation and IR in the skeletal muscle, with miR-221-3p as a key modulator of macrophage polarization.

Keywords:  aerobic exercise; insulin resistance; macrophage polarization; miR-221-3p; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2025.1534911
Nat Commun. 2025 Mar 07. 16(1): 1645

An obesogenic FTO allele causes accelerated development, growth and insulin resistance in human skeletal muscle cells.

Lu Guang, Shilin Ma, Ziyue Yao, Dan Song, Yu Chen, Shuqing Liu, Peng Wang, Jiali Su, Yuefan Wang, Lanfang Luo, Ng Shyh-Chang.

Human GWAS have shown that obesogenic FTO polymorphisms correlate with lean mass, but the mechanisms have remained unclear. It is counterintuitive because lean mass is inversely correlated with obesity and metabolic diseases. Here, we use CRISPR to knock-in FTOrs9939609-A into hESC-derived tissue models, to elucidate potentially hidden roles of FTO during development. We find that among human tissues, FTOrs9939609-A most robustly affect human muscle progenitors' proliferation, differentiation, senescence, thereby accelerating muscle developmental and metabolic aging. An edited FTOrs9939609-A allele over-stimulates insulin/IGF signaling via increased muscle-specific enhancer H3K27ac, FTO expression and m6A demethylation of H19 lncRNA and IGF2 mRNA, with excessive insulin/IGF signaling leading to insulin resistance upon replicative aging or exposure to high fat diet. This FTO-m6A-H19/IGF2 circuit may explain paradoxical GWAS findings linking FTOrs9939609-A to both leanness and obesity. Our results provide a proof-of-principle that CRISPR-hESC-tissue platforms can be harnessed to resolve puzzles in human metabolism.

DOI: https://doi.org/10.1038/s41467-024-53820-2
Nat Commun. 2025 Mar 08. 16(1): 2338

Mitochondrial damage in muscle specific PolG mutant mice activates the integrated stress response and disrupts the mitochondrial folate cycle.

Simon T Bond, Emily J King, Shannen M Walker, Christine Yang, Yingying Liu, Kevin H Liu, Aowen Zhuang, Aaron W Jurrjens, Haoyun A Fang, Luke E Formosa, Artika P Nath, Sergio Ruiz Carmona, Michael Inouye, Thy Duong, Kevin Huynh, Peter J Meikle, Simon Crawford, Georg Ramm, Sheik Nadeem Elahee Doomun, David P de Souza, Danielle L Rudler, Anna C Calkin, Aleksandra Filipovska, David W Greening, Darren C Henstridge, Brian G Drew.

During mitochondrial damage, information is relayed between the mitochondria and nucleus to coordinate precise responses to preserve cellular health. One such pathway is the mitochondrial integrated stress response (mtISR), which is known to be activated by mitochondrial DNA (mtDNA) damage. However, the causal molecular signals responsible for activation of the mtISR remain mostly unknown. A gene often associated with mtDNA mutations/deletions is Polg1, which encodes the mitochondrial DNA Polymerase γ (PolG). Here, we describe an inducible, tissue specific model of PolG mutation, which in muscle specific animals leads to rapid development of mitochondrial dysfunction and muscular degeneration in male animals from ~5 months of age. Detailed molecular profiling demonstrated robust activation of the mtISR in muscles from these animals. This was accompanied by striking alterations to enzymes in the mitochondrial folate cycle that was likely driven by a specific depletion in the folate cycle metabolite 5,10 methenyl-THF, strongly implying imbalanced folate intermediates as a previously unrecognised pathology linking the mtISR and mitochondrial disease.

DOI: https://doi.org/10.1038/s41467-025-57299-3
Aging Cell. 2025 Mar 10. e70002

Serum Proteomic and Metabolomic Signatures of High Versus Low Physical Function in Octogenarians.

Ceereena Ubaida-Mohien, Ruin Moaddel, Sally Spendiff, Norah J MacMillan, Marie-Eve Filion, Jose A Morais, Julián Candia, Liam F Fitzgerald, Tanja Taivassalo, Paul M Coen, Luigi Ferrucci, Russell T Hepple.

  Physical function declines with aging, yet there is considerable heterogeneity, with some individuals declining very slowly while others experience accelerated functional decline. To gain insight into mechanisms promoting high physical function with aging, we performed proteomics, targeted metabolomics, and targeted kynurenine-focused metabolomic analyses on serum specimens from three groups of octogenarians: High-functioning master athletes (HF, n = 16), healthy normal-functioning non-athletes (NF, n = 12), and lower functioning non-athletes (LF, n = 11). Higher performance status was associated with evidence consistent with: Lower levels of circulating proinflammatory markers, as well as unperturbed tryptophan metabolism, with the normal function of the kynurenic pathway; higher circulating levels of lysophosphatidylcholines that have been previously associated with better mitochondrial oxidative capacity; lower activity of the integrated stress response; lower levels of circulating SASP protein members; and lower levels of proteins that reflect neurodegeneration/denervation. Extending the observations of previous studies focused on the biomarkers of aging that predict poor function, our findings show that many of the same biomarkers associated with poor function exhibit attenuated changes in those who maintain a high function. Because of the cross-sectional nature of this study, results should be interpreted with caution, and bidirectional causality, where physical activity behavior is both a cause and outcome of differences in the biomarker changes, remains a possible interpretation.

Keywords:  SASP; aging; high functioning; inflammation; integrated stress response; kynurenine; low functioning; master athletes; mitochondria; serum proteomics

DOI:  https://doi.org/10.1111/acel.70002
Cells. 2025 Mar 05. pii: 379. [Epub ahead of print]14(5):

MiR-34b Regulates Muscle Growth and Development by Targeting SYISL.

Yuting Wu, Xiao Liu, Yonghui Fan, Hao Zuo, Xiaoyu Niu, Bo Zuo, Zaiyan Xu.

  Non-coding genes, such as microRNA and lncRNA, which have been widely studied, play an important role in the regulatory network of skeletal muscle development. However, the functions and mechanisms of most non-coding RNAs in skeletal muscle regulatory networks are unclear. This study investigated the function and mechanism of miR-34b in muscle growth and development. MiR-34b overexpression and interference tests were performed in C2C12 myoblasts and animal models. It was demonstrated that miR-34b significantly promoted mouse muscle growth and development in vivo, while miR-34b inhibited myoblast proliferation and promoted myoblast differentiation in vitro. Bioinformatics prediction using TargetScan for miRNA target identification and Bibiserv2 for potential miRNA-gene interaction analysis revealed a miR-34b binding site in the SYlSL sequence. The molecular mechanism of miR-34b regulating muscle growth and development was studied by co-transfection experiment, luciferase reporter gene detection, RNA immunoprecipitation, and RNA pull-down. MiR-34b can directly bind to SYISL and AGO2 proteins and regulate the expression of SYISL target genes p21 and MyoG by targeting SYISL, thereby regulating muscle growth and development. This study highlights that, as a novel regulator of myogenesis, miR-34b regulates muscle growth and development by targeting SYISL.

Keywords:  SYISL; differentiation; miR-34b; myoblast; proliferation

DOI:  https://doi.org/10.3390/cells14050379