bims-moremu 2025-03-30 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–03–30
23 papers selected by
Anna Vainshtein, Craft Science Inc.

Deciphering the role of IGFBP5 in delaying fibrosis and sarcopenia in aging skeletal muscle: therapeutic implications and molecular mechanisms.
Macrophage Subpopulation Promotes Skeletal Muscle Regeneration Through HGF/MET Signaling-Mediated Skeletal Muscle Stem Cell Proliferation.
Potential of synergist ablation to study mechanisms of skeletal muscle hypertrophy in rodent disease models.
Loss of Skeletal Muscle Inositol Polyphosphate Multikinase Disrupts Glucose Regulation and Limits Exercise Capacity.
From Earth to orbit: How to preserve muscle health in space and bed rest.
Mechanotransduction and Skeletal Muscle Atrophy: The Interplay Between Focal Adhesions and Oxidative Stress.
Dnmt3a overexpression disrupts skeletal muscle homeostasis, promotes an aging-like phenotype, and reduces metabolic elasticity.
Extracellular Vesicles from Regenerating Skeletal Muscle Mitigate Muscle Atrophy in an Amyotrophic Lateral Sclerosis Mouse Model.
MAP Kinase Phosphatase-5 Deficiency Improves Endurance Exercise Capacity.
Human Myobundle Platform for Studying the Role of Notch Signaling in Satellite Cell Phenotype and Function.
Control of circadian muscle glucose metabolism through the BMAL1-HIF axis in obesity.
Vitamin A-Retinoic Acid Contributes to Muscle Stem Cell andMitochondrial Function Loss in Old Age.
Gold nanoparticles modulate macrophage polarization to promote skeletal muscle regeneration.
Growth hormone-deficient Ames dwarf mice resist sarcopenia and exhibit enhanced endurance running performance at 24 months.
Biological sex does not impact intrinsic mitochondrial respiration supported by complexes I and II in human skeletal muscle.
Endurance exercise with reduced muscle glycogen content influences substrate utilization and attenuates acute mTORC1- and autophagic signaling in human type I and type II muscle fibers.
Physical training reduces cell senescence and associated insulin resistance in skeletal muscle.
Action and therapeutic targets of folliculin interacting protein 1: a novel signaling mechanism in redox regulation.
Skeletal muscle preservation in arctic ground squirrels during hibernation season.
Bile acid signaling in skeletal muscle homeostasis: from molecular mechanisms to clinical applications.
Testosterone/androgen receptor antagonizes immobility-induced muscle atrophy through Inhibition of myostatin transcription and inflammation in mice.
Bioinformatics and machine learning approaches to explore key biomarkers in muscle aging linked to adipogenesis.
Chloroquine Causes Aging-like Changes in Diaphragm Neuromuscular Junction Morphology in Mice.

Front Pharmacol. 2025 ;16 1557703

Deciphering the role of IGFBP5 in delaying fibrosis and sarcopenia in aging skeletal muscle: therapeutic implications and molecular mechanisms.

Luze Shi, Zheci Ding, Jiwu Chen.

   Introduction: Sarcopenia is a condition characterized by the loss of muscle fibers and excessive deposition of extracellular matrix proteins. The interplay between muscle atrophy and fibrosis is a central feature of sarcopenia. While the mechanisms underlying skeletal muscle aging and fibrosis remain incompletely understood, cellular senescence has emerged as a key contributor. This study investigates the role of D-galactose (D-gal) in inducing fibroblasts senescence and skeletal muscle fibrosis, and aims to find the key regulator of the process to serve as a therapeutical target.
Methods: To discover the role of D-gal in inducing cellular senescence and fibrosis, the senescence markers and the expression of fibrosis-related proteins were assessed after introducing D-gal among fibroblasts, and muscle strength and mass. The severity of muscle atrophy and fibrosis were also verified by using H&E staining and Masson trichrome staining after D-gal treatment via subcutaneous injection among mice. Subsequently, mRNA sequencing (RNA-seq) was performed and the differential expressed genes were identified between under D-gal or control treatment, to discover the key regulator of D-GAL-driven fibroblasts senescence and fibrosis. The role of the key regulator IGFBP5 were then validated in D-GAL treated IGFBP5-knockdown fibroblasts in vitro by analyzing the level of senescence and fibrosis-related markers. And the results were further confirmed in vivo in IGFBP5-knockdown SAMP8 mice with histological examinations.
Results: D-gal treatment effectively induced cellular senescence and fibrosis in fibroblasts, as well as skeletal muscle atrophy, fibrosis and loss in muscle mass and function in mice. IGFBP5 was identified as a key regulator of D-GAL induced senescence and fibrosis among fibroblasts using RNA-seq. And further validation tests showed that IGFBP5-knockdown could alleviate D-GAL-induced fibroblast cellular senescence and fibrosis, as well as the severity of muscle atrophy and fibrosis in SAMP8 mice.
Discussion: IGFBP5 emerging as a key regulator of D-GAL-induced fibroblast cellular senescence and fibrosis. The findings provide new insights into the molecular mechanisms underlying age-related skeletal muscle fibrosis and highlight IGFBP5 as a potential therapeutic target. Further research is needed to validate these findings and explore related clinical applications.

Keywords:  fibrosis; sarcopenia; skeletal muscle aging; skeletal muscle fibroblasts; skeletal muscle fibrosis

DOI:  https://doi.org/10.3389/fphar.2025.1557703
Aging Cell. 2025 Mar 25. e70042

Macrophage Subpopulation Promotes Skeletal Muscle Regeneration Through HGF/MET Signaling-Mediated Skeletal Muscle Stem Cell Proliferation.

Hiroyuki Koike, Miho Sugimura, Rie Ouchi, Yuki Yoshimoto, Ichiro Manabe, Yumiko Oishi.

  Macrophages are key regulators of skeletal muscle regeneration, yet the specific macrophage subpopulations responsible for this process and their cell-cell interactions remain insufficiently understood, as does the mechanism underlying age-related impairment of skeletal muscle regeneration. We utilized single-cell RNA sequencing to identify transcriptionally distinct macrophage subpopulations within skeletal muscle from young (8-week-old) and aged (24-month-old) mice. Among them, the Mac_1 subpopulation interacted with muscle satellite cells (MuSCs) and promoted their proliferation through HGF/c-Met signaling that suppressed Cdkn1b expression. This interaction was critical for efficient muscle regeneration in vivo and in a 3D-muscle organoid model. The age-related decline in muscle regeneration was associated with reduced HGF expression in Mac_1 macrophages. Administration of exogenous HGF to aged mice and macrophage-depleted young mice partially rescued the impaired muscle regeneration. This study elucidates a mechanism of skeletal muscle regeneration that offers insight into potential strategies for preventing and treating skeletal muscle diseases, including sarcopenia.

Keywords:  macrophage; organoid; regeneration; single‐cell RNA‐sequence; skeletal muscle stem cells

DOI:  https://doi.org/10.1111/acel.70042
Am J Physiol Cell Physiol. 2025 Mar 24.

Potential of synergist ablation to study mechanisms of skeletal muscle hypertrophy in rodent disease models.

Fabio Sarto, Christopher S Fry, Marco V Narici, Lee Rubin, Feodor D Price.

  Synergist ablation (SA) is a well-established model of mechanical overload-induced hypertrophy in rodents, commonly used to infer skeletal muscle adaptation to resistance training in humans. Given the critical role of skeletal muscle atrophy in chronic conditions such as neuromuscular, metabolic, and cardiopulmonary disorders, SA represents a promising preclinical tool to study muscle hypertrophy mechanisms in pathological states. However, while extensively characterized in healthy animals, the potential applications of SA in disease models remain largely overlooked. This Mini-Review summarizes existing studies employing SA in rodent disease models, highlighting the diverse hypertrophic responses observed across conditions, including Duchenne muscular dystrophy, obesity, diabetes, cancer cachexia, and chronic kidney disease. Although hypertrophy gains are generally attenuated in diseased animals compared to healthy controls, SA-induced overload provides valuable insights into disease-specific regulatory mechanisms, including alterations in intracellular signaling, fiber-type transitions, and disease phenotype. We also discuss the strengths and limitations of SA as a preclinical model for resistance training in disease contexts and propose its broader adoption for mechanistic investigations into skeletal muscle plasticity under pathological conditions.

Keywords:  Cancer Cachexia; Exercise; Metabolic Disorders; Neuromuscular Disorders; Resistance Training

DOI:  https://doi.org/10.1152/ajpcell.00076.2025
Int J Mol Sci. 2025 Mar 07. pii: 2395. [Epub ahead of print]26(6):

Loss of Skeletal Muscle Inositol Polyphosphate Multikinase Disrupts Glucose Regulation and Limits Exercise Capacity.

Ji-Hyun Lee, Ik-Rak Jung, Becky Tu-Sekine, Sunghee Jin, Frederick Anokye-Danso, Rexford S Ahima, Sangwon F Kim.

  Inositol phosphates are critical signaling messengers involved in a wide range of biological pathways, and inositol polyphosphate multikinase (IPMK) functions as a rate-limiting enzyme for inositol polyphosphate metabolism. IPMK has been implicated in cellular metabolism, but its function at the systemic level is still poorly understood. Since skeletal muscle is a major contributor to energy homeostasis, we have developed a mouse model in which skeletal muscle IPMK is specifically deleted and examined how a loss of IPMK affects whole-body metabolism. Here, we report that skeletal-muscle-specific IPMK knockout mice exhibited a ~12% increase in body weight compared to WT controls (p < 0.05). These mice also showed a significantly impaired glucose tolerance, as indicated by their ~50% higher blood glucose levels during GTT. Additionally, exercise capacity was reduced by ~45% in IPMK-MKO mice, demonstrating a decline in endurance. Moreover, these metabolic alterations were accompanied by a 2.5-fold increase in skeletal muscle triglyceride accumulation, suggesting impaired lipid metabolism. Further analysis revealed that IPMK-deficient myocytes exhibited 30% lower β-oxidation rates. Thus, our results suggest that IPMK mediates whole-body metabolism by regulating muscle metabolism and may be potentially targeted for the treatment of metabolic syndromes.

Keywords:  IPMK; exercise; inositol polyphosphate; insulin; skeletal muscle

DOI:  https://doi.org/10.3390/ijms26062395
Exp Physiol. 2025 Mar 26.

From Earth to orbit: How to preserve muscle health in space and bed rest.

Antonios Matsakas, Colleen Deane.



Keywords:  atrophy; bed rest; exercise; skeletal muscle; spaceflight

DOI:  https://doi.org/10.1113/EP092729
Int J Mol Sci. 2025 Mar 20. pii: 2802. [Epub ahead of print]26(6):

Mechanotransduction and Skeletal Muscle Atrophy: The Interplay Between Focal Adhesions and Oxidative Stress.

Khaled Y Kamal, Marina Trombetta-Lima.

  Mechanical unloading leads to profound musculoskeletal degeneration, muscle wasting, and weakness. Understanding the specific signaling pathways involved is essential for uncovering effective interventions. This review provides new perspectives on mechanotransduction pathways, focusing on the critical roles of focal adhesions (FAs) and oxidative stress in skeletal muscle atrophy under mechanical unloading. As pivotal mechanosensors, FAs integrate mechanical and biochemical signals to sustain muscle structural integrity. When disrupted, these complexes impair force transmission, activating proteolytic pathways (e.g., ubiquitin-proteasome system) that accelerate atrophy. Oxidative stress, driven by mitochondrial dysfunction and NADPH oxidase-2 (NOX2) hyperactivation, exacerbates muscle degeneration through excessive reactive oxygen species (ROS) production, impaired repair mechanisms, and dysregulated redox signaling. The interplay between FA dysfunction and oxidative stress underscores the complexity of muscle atrophy pathogenesis: FA destabilization heightens oxidative damage, while ROS overproduction further disrupts FA integrity, creating a self-amplifying vicious cycle. Therapeutic strategies, such as NOX2 inhibitors, mitochondrial-targeted antioxidants, and FAK-activating compounds, promise to mitigate muscle atrophy by preserving mechanotransduction signaling and restoring redox balance. By elucidating these pathways, this review advances the understanding of muscle degeneration during unloading and identifies promising synergistic therapeutic targets, emphasizing the need for combinatorial approaches to disrupt the FA-ROS feedback loop.

Keywords:  NADPH oxidases; focal adhesions; mechanotransduction; muscle atrophy; oxidative stress; redox biology; skeletal muscles; therapeutic interventions

DOI:  https://doi.org/10.3390/ijms26062802
iScience. 2025 Apr 18. 28(4): 112144

Dnmt3a overexpression disrupts skeletal muscle homeostasis, promotes an aging-like phenotype, and reduces metabolic elasticity.

Mamoru Oyabu, Yuto Ohira, Mariko Fujita, Kiyoshi Yoshioka, Runa Kawaguchi, Atsushi Kubo, Yukino Hatazawa, Hinako Yukitoshi, Huascar Pedro Ortuste Quiroga, Naoki Horii, Fumihito Miura, Hiromitsu Araki, Masaki Okano, Izuho Hatada, Hitoshi Gotoh, Tatsuya Yoshizawa, So-Ichiro Fukada, Yoshihiro Ogawa, Takashi Ito, Kengo Ishihara, Yusuke Ono, Yasutomi Kamei.

  Mammalian aging is reportedly driven by the loss of epigenetic information; however, its impact on skeletal muscle aging remains unclear. This study shows that aging mouse skeletal muscle exhibits increased DNA methylation, and overexpression of DNA methyltransferase 3a (Dnmt3a) induces an aging-like phenotype. Muscle-specific Dnmt3a overexpression leads to an increase in central nucleus-positive myofibers, predominantly in fast-twitch fibers, a shift toward slow-twitch fibers, elevated inflammatory and senescence markers, mitochondrial OXPHOS complex I reduction, and decreased basal autophagy. Dnmt3a overexpression resulted in reduced muscle mass and strength and impaired endurance exercise capacity with age, accompanied by an enhanced inflammatory signature. In addition, Dnmt3a overexpression reduced not only sensitivity to starvation-induced muscle atrophy but also the restorability from muscle atrophy. These findings suggest that increased DNA methylation disrupts skeletal muscle homeostasis, promotes an aging-like phenotype, and reduces muscle metabolic elasticity.

Keywords:  Age; Epigenetics; Integrative aspects of cell biology; Model organism; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2025.112144
Cells. 2025 Mar 20. pii: 464. [Epub ahead of print]14(6):

Extracellular Vesicles from Regenerating Skeletal Muscle Mitigate Muscle Atrophy in an Amyotrophic Lateral Sclerosis Mouse Model.

Jinghui Gao, Aria Sikal, Rachel Hankin, Yaochao Zheng, Elijah Sterling, Kenny Chan, Yao Yao.

  Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease characterized by progressive motor neuron degeneration and muscle atrophy, with no effective treatments available. Chronic inflammation, which impairs muscle regeneration and promotes proteolysis, is a key contributor to ALS-related muscle atrophy and a promising therapeutic target. Here, we applied extracellular vesicles (EVs) derived from regenerating skeletal muscles 14 days post-acute injury (CTXD14SkM-EVs), which possess a unique anti-inflammatory profile, to target muscle defects in ALS. We found that CTXD14SkM-EVs enhanced myoblast differentiation and fusion in a cellular muscle-wasting model induced by pro-inflammatory cytokine tumor necrosis factor alpha. Intramuscular administration of these EVs into an ALS mouse model mitigated muscle atrophy by promoting muscle regeneration, shifting macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 state, and suppressing the aberrant Nuclear Factor Kappa B (NF-κB) signaling, a key driver of muscle protein degradation. These results underscore the therapeutic potential of regenerating muscle-derived EVs for combating muscle atrophy in ALS.

Keywords:  amyotrophic lateral sclerosis; extracellular vesicles; muscle atrophy; regenerating skeletal muscle

DOI:  https://doi.org/10.3390/cells14060464
Cells. 2025 Mar 11. pii: 410. [Epub ahead of print]14(6):

MAP Kinase Phosphatase-5 Deficiency Improves Endurance Exercise Capacity.

Jaime A Perales, Ahmed Lawan, Sudip Bajpeyi, Sung Min Han, Anton M Bennett, Kisuk Min.

  Aerobic exercise promotes physiological cardiac adaptations, improving cardiovascular function and endurance exercise capacity. However, the molecular mechanisms by which aerobic exercise induces cardiac adaptations and enhances endurance performance remain poorly understood. Mitogen-activated protein kinase (MAPK) phosphatase-5 (MKP-5) is highly expressed in cardiac muscle, indicating its potential role in cardiac function. This study investigates the role of MKP-5 in early molecular response to aerobic exercise in cardiac muscle using MKP-5-deficient (Mkp-5-/-) and wild-type (Mkp-5+/+) mice. Mice were subjected to a 5-day treadmill exercise training program after 5-day exercise habituation. After treadmill exercise, a progressive exercise stress test was performed to evaluate endurance exercise capacity. Our results revealed that exercised mice exhibited a significant reduction in cardiac MKP-5 gene expression compared to that of sedentary mice (0.19 ± 5.89-fold; p < 0.0001). Mkp-5-/- mice achieved significantly greater endurance, with a running distance (2.81 ± 169.8-fold; p < 0.0429) longer than Mkp-5+/+ mice. Additionally, MKP-5 deficiency enhanced Akt/mTOR signaling (p-Akt/Akt: 1.29 ± 0.12-fold; p = 0.04; p-mTOR/mTOR: 1.59 ± 0.14-fold; p = 0.002) and mitochondrial biogenesis (pgc-1α: 1.56 ± 0.27-fold; p = 0.03) in cardiac muscle in response to aerobic exercise. Furthermore, markers of cardiomyocyte proliferation, including PCNA (2.24 ± 0.31-fold; p < 0.001), GATA4 (1.47 ± 0.10-fold; p < 0.001), and CITED4 (2.03 ± 0.15-fold; p < 0.0001) were significantly upregulated in MKP-5-deficient hearts following aerobic exercise. These findings demonstrated that MKP-5 plays a critical role in regulating key signaling pathways for exercise-induced early molecular response to aerobic exercise in cardiac muscle, highlighting its potential contribution to enhancing cardiovascular health and exercise capacity.

Keywords:  MKP-5; aerobic exercise; cardiomyocyte proliferation; mitochondrial biogenesis

DOI:  https://doi.org/10.3390/cells14060410
Adv Healthc Mater. 2025 Mar 24. e2404695

Human Myobundle Platform for Studying the Role of Notch Signaling in Satellite Cell Phenotype and Function.

Torie Broer, Nick Tsintolas, Stewart Hammond, Abbigail Helfer, Joonbum Lee, Karly Purkey, Sophia DeLuca, Alastair Khodabukus, Nenad Bursac.

  Notch signaling plays a pivotal role in regulating satellite cell (SC) behavior during skeletal muscle development, homeostasis, and repair. While well-characterized in mouse models, the impact of Notch signaling in human muscle tissues remains largely underexplored. Here, a 3D tissue-engineered model of human skeletal muscle ("myobundles") is utilized as an in vitro platform for temporal control and studies of Notch singaling. Myofiber-specific overexpression of the Notch ligand, DLL1, early in myobundle differentiation increases the abundance of 3D SCs and shifts their phenotype to a more quiescent-like state, along with decreasing muscle mass and function. In contrast, myofiber-specific DLL1 overexpression after one week of myobundle differentiation does not affect 3D SC abundance or muscle function, but increases transcriptomic markers of SC quiescence, confirming the temporal dependence of SC activation and self-renewal on Notch signaling activity. Finally, for the first time these studies show that even after a transient, myofiber-specific upregulation of Notch signaling in myobundles, 3D SCs expanded from these tissues can re-form functional "secondary" myobundles containing an amplified SC pool. Future studies in the described human myobundle platform are expected to aid the development of novel Notch-targeted therapies for muscular dystrophies and aging.

Keywords:  DLL1; muscle stem cell; notch signaling; skeletal muscle; tissue engineering

DOI:  https://doi.org/10.1002/adhm.202404695
Proc Natl Acad Sci U S A. 2025 Apr;122(13): e2424046122

Control of circadian muscle glucose metabolism through the BMAL1-HIF axis in obesity.

Claire A Chaikin, Abhishek V Thakkar, Adam W T Steffeck, Eric M Pfrender, Kaitlyn Hung, Pei Zhu, Nathan J Waldeck, Rino Nozawa, Weimin Song, Christopher R Futtner, Mattia Quattrocelli, Joseph Bass, Issam Ben-Sahra, Clara B Peek.

  Disruptions of circadian rhythms are widespread in modern society and lead to accelerated and worsened symptoms of metabolic syndrome. In healthy mice, the circadian clock factor BMAL1 is required for skeletal muscle function and metabolism. However, the importance of muscle BMAL1 in the development of metabolic diseases, such as diet-induced obesity (DIO), remains unclear. Here, we demonstrate that skeletal muscle-specific BMAL1-deficient mice exhibit worsened glucose tolerance upon high-fat diet feeding, despite no evidence of increased weight gain. Metabolite profiling from Bmal1-deficient muscles revealed impaired glucose utilization specifically at early steps in glycolysis that dictate the switch between anabolic and catabolic glucose fate. We provide evidence that this is due to abnormal control of the nutrient stress-responsive hypoxia-inducible factor (HIF) pathway. Genetic HIF1α stabilization in muscle Bmal1-deficient mice restores glucose tolerance and expression of 217/736 dysregulated genes during DIO, including glycolytic enzymes. Together, these data indicate that during DIO, skeletal muscle BMAL1 is an important regulator of HIF-driven glycolysis and metabolic flexibility, which influences the development of high-fat-diet-induced glucose intolerance.

Keywords:  circadian rhythm; diet-induced obesity; hypoxia; skeletal muscle

DOI:  https://doi.org/10.1073/pnas.2424046122
JCI Insight. 2025 Mar 25. pii: e183706. [Epub ahead of print]

Vitamin A-Retinoic Acid Contributes to Muscle Stem Cell andMitochondrial Function Loss in Old Age.

Paula M Fraczek, Pamela Duran, Benjamin A Yang, Valeria Ferre, Leanne Alawieh, Jesus A Castor-Macias, Vivian T Wong, Steve D Guzman, Celeste Piotto, Klimentini Itsani, Jacqueline A Larouche, Carlos A Aguilar.

  Adult stem cells decline in number and function in old age and identifying factors that can delay or revert age-associated adult stem cell dysfunction are vital for maintaining healthy lifespan. Here we show that Vitamin A, a micronutrient that is derived from diet and metabolized into retinoic acid, acts as an antioxidant and transcriptional regulator in muscle stem cells. We first show that obstruction of dietary Vitamin A in young animals drives mitochondrial and cell cycle dysfunction in muscle stem cells that mimics old age. Next, we pharmacologically targeted retinoic acid signaling in myoblasts and aged muscle stem cells ex vivo and in vivo and observed reductions in oxidative damage, enhanced mitochondrial function, and improved maintenance of quiescence through fatty acid oxidation. We next detected the receptor for vitamin A derived retinol, stimulated by retinoic acid 6 or Stra6, was diminished with muscle stem cell activation and in old age. To understand the relevance of Stra6 loss, we knocked down Stra6 and observed an accumulation of mitochondrial reactive oxygen species, as well as changes in mitochondrial morphology and respiration. These results demonstrate that Vitamin A regulates mitochondria and metabolism in muscle stem cells and highlight a unique mechanism connecting stem cell function with vitamin intake.

Keywords:  Adult stem cells; Aging; Muscle; Muscle biology; Stem cells

DOI:  https://doi.org/10.1172/jci.insight.183706
Mater Today Bio. 2025 Jun;32 101653

Gold nanoparticles modulate macrophage polarization to promote skeletal muscle regeneration.

Lining Xu, Jiahuang Qiu, Quanzhong Ren, Dingding Wang, Anyi Guo, Ling Wang, Kedong Hou, Renxian Wang, Yajun Liu.

  Skeletal muscle regeneration is a complex process that depends on the interplay between immune responses and muscle stem cell (MuSC) activity. Macrophages play a crucial role in this process, exhibiting distinct polarization states-M1 (pro-inflammatory) and M2 (anti-inflammatory)-that significantly affect tissue repair outcomes. Recent advancements in nanomedicine have positioned gold nanoparticles (Au NPs) as promising tools for modulating macrophage polarization and enhancing muscle regeneration. This review examines the role of Au NPs in influencing macrophage behavior, focusing on their physicochemical properties, biocompatibility, and mechanisms of action. We discuss how Au NPs can promote M2 polarization, facilitating tissue repair through modulation of cytokine production, interaction with cell surface receptors, and activation of intracellular signaling pathways. Additionally, we highlight the benefits of Au NPs on MuSC function, angiogenesis, and extracellular matrix remodeling. Despite the potential of Au NPs in skeletal muscle regeneration, challenges remain in optimizing nanoparticle design, developing targeted delivery systems, and understanding long-term effects. Future directions should focus on personalized medicine approaches and combination therapies to enhance therapeutic efficacy. Ultimately, this review emphasizes the transformative potential of Au NPs in regenerative medicine, offering hope for improved treatments for muscle injuries and diseases.

Keywords:  Gold nanoparticles; Immunomodulation; Macrophage polarization; Skeletal muscle regeneration

DOI:  https://doi.org/10.1016/j.mtbio.2025.101653
Geroscience. 2025 Mar 26.

Growth hormone-deficient Ames dwarf mice resist sarcopenia and exhibit enhanced endurance running performance at 24 months.

Matthew J Johnston, Sharlene G Rakoczy, LaDora V Thompson, Holly M Brown-Borg.

  Ames dwarf mice (df/df) live 50% longer than normal littermates due to a genetic defect in growth hormone (GH) signaling. The enhanced longevity of Ames dwarfs has been studied extensively in an endocrinological context of cellular metabolism and increased resistance to oxidative stress (Bartke. World J Mens Health 37(1):19, 8; Bartke 2; BartkeJ Am Aging Assoc 23(4):219, 10; Bartke. World J Mens Health 39(3):454-465, 11; Brown-Borg et al. Nature 384(6604):33-33, 1; Masternak et al. 2018). However, the skeletal muscle system is relatively unexplored, the quality of which dictates metabolic homeostasis, permits movement and exercise, and exerts paracrine effects on other organs (Delmonico and Beck Am J Lifestyle Med 11(2):167-181, 25; Evans et al. GeroScience 46(1):183, 26; Kim and Kim. Endocrinol Metab (Seoul) 35(1):1-6, 15; Masternak et al. 2018). Here, we characterize the fitness capacity and skeletal muscle morphology of Ames mice to determine if previously established longevous effects of GH deficiency extend to skeletal muscle tissue. Mutually exclusive, age-matched cohorts of male Ames mice and wildtype controls performed grip strength, rotarod, and endurance running experiments over 6 months. The largest difference in physical performance was observed in endurance running capacity, where dwarf mice outperformed wildtype controls increasingly with age. Tibialis anterior (TA) muscles were evaluated for myofiber size, quality, and environment. Ames mice show reduced myofiber cross-sectional area (CSA) paired with increased myofibers per muscle. Dwarf myofiber populations are less heterogenous in size and seemingly resist sarcopenia, as skeletal muscle from aged individuals shows youthful morphological resemblance in mean myofiber CSA, size frequency distribution, and presence of fibrotic tissue. Declines in fitness performance and myofiber integrity were observable in age-matched wildtype controls. Utilizing an established longevity model to investigate skeletal muscle function and morphology is a novel approach to gaining insight into the seemingly inverse relationship between GH signaling and mammalian longevity.

Keywords:  Aging; Exercise; Growth hormone; Muscle; Sarcopenia

DOI:  https://doi.org/10.1007/s11357-025-01630-9
Exp Physiol. 2025 Mar 26.

Biological sex does not impact intrinsic mitochondrial respiration supported by complexes I and II in human skeletal muscle.

Emily J Ferguson, Lauren J Pacitti, Justin Bureau, Callum J Pufahl, Eveline Menezes, Tanner Stokes, Shivam Gandhi, Luca J Delfinis, Craig A Simpson, Christopher G R Perry, Brendon J Gurd, Chris McGlory.

  The effect of biological sex on rates of skeletal muscle mitochondrial respiration supported by creatine-dependent phosphate shuttling was previously unknown. The aim of this investigation was to test the hypothesis that females and males matched for peak oxygen uptake normalized to fat-free mass would not exhibit differences in rates of mass-specific and intrinsic mitochondrial respiration in the presence or absence of creatine. Rates of mass-specific and intrinsic complex I (pyruvate and malate)- and complex I+II-supported, adenosine diphosphate (ADP)-stimulated mitochondrial respiration in the presence and absence of 20 mM creatine were measured via high-resolution respirometry. Total, intermyofibrillar and subsarcolemmal mitochondrial volume density were analysed using transmission electron microscopy. Rates of intrinsic mitochondrial respiration were obtained by normalizing mass-specific respiration rates to total mitochondrial volume density and total electron transport chain subunit protein content. Overall, there was no effect of sex on rates of mass-specific or intrinsic mitochondrial respiration in the presence or absence of creatine. There was also no effect of sex on total, intermyofibrillar and subsarcolemmal mitochondrial volume density or electron transport chain subunit protein content. Our data demonstrate an overall lack of sex-based differences in rates of intrinsic complex I- and complex I+II-supported, ADP-stimulated mitochondrial respiration in the presence or absence of creatine in females and males matched for aerobic fitness. Thus, biological sex per se does not appear to modulate intrinsic skeletal muscle mitochondrial respiration in healthy young adults.

Keywords:  aerobic fitness; biological sex; creatine; human skeletal muscle; intrinsic mitochondrial respiration; mitochondrial content

DOI:  https://doi.org/10.1113/EP092551
Skelet Muscle. 2025 Mar 25. 15(1): 9

Endurance exercise with reduced muscle glycogen content influences substrate utilization and attenuates acute mTORC1- and autophagic signaling in human type I and type II muscle fibers.

Oscar Horwath, Lucas Cornet, Henrik Strömlind, Marcus Moberg, Sebastian Edman, Karin Söderlund, Antonio Checa, Jorge L Ruas, Eva Blomstrand.

   BACKGROUND: Exercising with low muscle glycogen content can improve training adaptation, but the mechanisms underlying the muscular adaptation are still largely unknown. In this study, we measured substrate utilization and cell signaling in different muscle fiber types during exercise and investigated a possible link between these variables.
METHODS: Five subjects performed a single leg cycling exercise in the evening (day 1) with the purpose of reducing glycogen stores. The following morning (day 2), they performed two-legged cycling at ∼70% of VO2peak for 1 h. Muscle biopsies were taken from both legs pre- and post-exercise for enzymatic analyses of glycogen, metabolite concentrations using LC-MS/MS-based quantification, and protein signaling using Western blot in pools of type I or type II fibers.
RESULTS: Glycogen content was 60-65% lower for both fiber types (P < 0.01) in the leg that exercised on day 1 (low leg) compared to the other leg with normal level of glycogen (normal leg) before the cycling exercise on day 2. Glycogen utilization during exercise was significantly less in both fiber types in the low compared to the normal leg (P < 0.05). In the low leg, there was a 14- and 6-fold increase in long-chain fatty acids conjugated to carnitine in type I and type II fibers, respectively, post-exercise. This increase was 3-4 times larger than in the normal leg (P < 0.05). Post-exercise, mTORSer2448 phosphorylation was increased in both fiber types in the normal leg (P < 0.05) but remained unchanged in both fiber types in the low leg together with an increase in eEF2Thr56 phosphorylation in type I fibers (P < 0.01). Exercise induced a reduction in the autophagy marker LC3B-II in both fiber types and legs, but the post-exercise level was higher in both fiber types in the low leg (P < 0.05). Accordingly, the LC3B-II/I ratio decreased only in the normal leg (75% for type I and 87% for type II, P < 0.01).
CONCLUSIONS: Starting an endurance exercise session with low glycogen availability leads to profound changes in substrate utilization in both type I and type II fibers. This may reduce the mTORC1 signaling response, primarily in type I muscle fibers, and attenuate the normally observed reduction in autophagy.

Keywords:  Autophagy; Fatty acids; Metabolomics; Muscle fiber type; mTORC1

DOI:  https://doi.org/10.1186/s13395-025-00377-3
Mol Metab. 2025 Mar 22. pii: S2212-8778(25)00037-7. [Epub ahead of print] 102130

Physical training reduces cell senescence and associated insulin resistance in skeletal muscle.

Agnieszka Podraza-Farhanieh, Rosa Spinelli, Federica Zatterale, Annika Nerstedt, Silvia Gogg, Matthias Blüher, Ulf Smith.

   BACKGROUND: Cellular senescence (CS) is a key aging process that leads to irreversible cell cycle arrest and an altered secretory phenotype. In skeletal muscle (SkM), the accumulation of senescent cells contributes to sarcopenia. Despite exercise being a known intervention for maintaining SkM function and metabolic health, its effects on CS remain poorly understood.
OBJECTIVES: This study aimed to investigate the impact of exercise on CS in human SkM by analyzing muscle biopsies from young, normal-weight individuals and middle-aged individuals with obesity, both before and after exercise intervention.
METHODS: Muscle biopsies were collected from both groups before and after an exercise intervention. CS markers, insulin sensitivity (measured with euglycemic clamp), and satellite cell markers were analyzed. Additionally, in vitro experiments were conducted to evaluate the effects of cellular senescence on human satellite cells, focusing on key regulatory genes and insulin signaling.
RESULTS: Individuals with obesity showed significantly elevated CS markers, along with reduced expression of GLUT4 and PAX7, indicating impaired insulin action and regenerative potential. Exercise improved insulin sensitivity, reduced CS markers, and activated satellite cell response in both groups. In vitro experiments revealed that senescence downregulated key regulatory genes in satellite cells and impaired insulin signaling by reducing the Insulin Receptor β-subunit.
CONCLUSIONS: These findings highlight the role of CS in regulating insulin sensitivity in SkM and underscore the therapeutic potential of exercise in mitigating age- and obesity-related muscle dysfunction. Targeting CS through exercise or senolytic agents could offer a promising strategy for improving metabolic health and combating sarcopenia, particularly in at-risk populations.

Keywords:  Aging; Cellular senescence; Exercise intervention; Obesity; Satellite cells; Skeletal muscles

DOI:  https://doi.org/10.1016/j.molmet.2025.102130
Front Cell Dev Biol. 2025 ;13 1523489

Action and therapeutic targets of folliculin interacting protein 1: a novel signaling mechanism in redox regulation.

Qingzhi Ran, Aoshuang Li, Bo Yao, Chunrong Xiang, Chunyi Qu, Yongkang Zhang, Xuanhui He, Hengwen Chen.

  Rapid activation of adenosine monophosphate-activated protein kinase (AMPK) induces phosphorylation of mitochondrial-associated proteins, a process by which phosphate groups are added to regulate mitochondrial function, thereby modulating mitochondrial energy metabolism, triggering an acute metabolic response, and sustaining metabolic adaptation through transcriptional regulation. AMPK directly phosphorylates folliculin interacting protein 1 (FNIP1), leading to the nuclear translocation of transcription factor EB (TFEB) in response to mitochondrial functions. While mitochondrial function is tightly linked to finely-tuned energy-sensing mobility, FNIP1 plays critical roles in glucose transport and sensing, mitochondrial autophagy, cellular stress response, and muscle fiber contraction. Consequently, FNIP1 emerges as a promising novel target for addressing aberrant mitochondrial energy metabolism. Recent evidence indicates that FNIP1 is implicated in mitochondrial biology through various pathways, including AMPK, mTOR, and ubiquitination, which regulate mitochondrial autophagy, oxidative stress responses, and skeletal muscle contraction. Nonetheless, there is a dearth of literature discussing the physiological mechanism of action of FNIP1 as a novel therapeutic target. This review outlines how FNIP1 regulates metabolic-related signaling pathways and enzyme activities, such as modulating mitochondrial energy metabolism, catalytic activity of metabolic enzymes, and the homeostasis of metabolic products, thereby controlling cellular function and fate in different contexts. Our focus will be on elucidating how these metabolite-mediated signaling pathways regulate physiological processes and inflammatory diseases.

Keywords:  autophagy; folliculin interacting protein 1; glucose sensing; intracellular metabolism; mitochondria; muscle fiber contraction; reductive stress

DOI:  https://doi.org/10.3389/fcell.2025.1523489
Comp Biochem Physiol A Mol Integr Physiol. 2025 Mar 21. pii: S1095-6433(25)00045-5. [Epub ahead of print]304 111847

Skeletal muscle preservation in arctic ground squirrels during hibernation season.

Anna V Goropashnaya, Inigo Yoldi Bergua, M Hoshi Sugiura, Sarah A Rice, Kelly L Drew, Esther E Dupont-Versteegden, Vadim B Fedorov.

  Reduced skeletal loading and inactivity leads to muscle atrophy in humans and most mammals. By contrast, hibernating mammals demonstrate limited loss of skeletal muscle mass and strength by the end of winter after being physically inactive for several months. The present study objective was to detect any signs of muscle atrophy and restoration in arctic ground squirrel (AGS) skeletal muscles during the hibernation season. Quadriceps muscles of juvenile AGS males were collected 1-2 weeks before hibernation, and at 2, 6, 10-12 and 16-22 weeks after onset of hibernation during interbout arousal when body temperature returns to euthermic level. Muscle mass, fiber cross-sectional area (CSA) and fiber type composition were determined, as well as total and ribosomal RNA content, and expression of key genes involved in protein degradation. We found that muscle mass, CSA and fiber size distribution were not different between the groups (P > 0.05). No difference was detected in myofiber composition between the hibernation groups compared to pre-hibernation. Total RNA and ribosomal RNA content were not significantly different between the groups during hibernation. Transcript levels of ubiquitin E3-ligase FBXO32 (Atrogin-1, MAFbx) and autophagy related genes MAP1LC3A and BECN1 were not different between the hibernation and pre-hibernation groups. However, ubiquitin E3-ligase TRIM63 (MuRF-1) was significantly higher expressed at 2 weeks of hibernation compared to the other timepoints. These results, for the first time, show that AGS preserve muscles during hibernation season.

Keywords:  Arctic ground squirrels; Gene expression; Hibernation; Muscle atrophy

DOI:  https://doi.org/10.1016/j.cbpa.2025.111847
Front Endocrinol (Lausanne). 2025 ;16 1551100

Bile acid signaling in skeletal muscle homeostasis: from molecular mechanisms to clinical applications.

Feng Jia, Xiangliang Liu, Yahui Liu.

  The intricate relationship between bile acid metabolism and skeletal muscle function has emerged as a crucial area of research in metabolic health. This review synthesizes current evidence highlighting the fundamental role of bile acids as key signaling molecules in muscle homeostasis and their therapeutic potential in muscle-related disorders. Recent advances in molecular biology and metabolomics have revealed that bile acids, beyond their classical role in lipid absorption, function as essential regulators of muscle mass and function through multiple signaling pathways, particularly via the nuclear receptor FXR and membrane receptor TGR5. Clinical studies have demonstrated significant associations between altered bile acid profiles and muscle wasting conditions, while experimental evidence has elucidated the underlying mechanisms linking bile acid signaling to muscle protein synthesis, energy metabolism, and regeneration capacity. We critically examine the emerging therapeutic strategies targeting bile acid pathways, including receptor-specific agonists, microbiome modulators, and personalized interventions based on individual bile acid profiles. Additionally, we discuss novel diagnostic approaches utilizing bile acid-based biomarkers and their potential in early detection and monitoring of muscle disorders. This review also addresses current challenges in standardization and clinical translation while highlighting promising future directions in this rapidly evolving field. Understanding the bile acid-muscle axis may provide new opportunities for developing targeted therapies for age-related muscle loss and metabolic diseases.

Keywords:  FXR; bile acids; biomarkers; sarcopenia; skeletal muscle; tgr5; therapeutic targets

DOI:  https://doi.org/10.3389/fendo.2025.1551100
Sci Rep. 2025 Mar 27. 15(1): 10568

Testosterone/androgen receptor antagonizes immobility-induced muscle atrophy through Inhibition of myostatin transcription and inflammation in mice.

Miya Oura, Bo-Kyung Son, Zehan Song, Koichi Toyoshima, Michiko Nanao-Hamai, Sumito Ogawa, Masahiro Akishita.

  Sarcopenia is caused by excessive muscle protein degradation owing to various factors, including disuse. Although testosterone supplementation is an effective treatment, the underlying molecular mechanisms, particularly the role of the androgen receptor (AR), remain unclear. In this study, we examined the preventive actions of testosterone/AR against muscle atrophy in a murine model of immobilization-induced muscle atrophy. The bilateral hindlimbs of 8-week-old male C57BL/6J mice were immobilized using a wire. Testosterone deficiency and supplementation (50 µg/mL) were conducted by castration and intraperitoneal injection (twice a week for a month), respectively. The results showed a remarkable decline in muscle mass and strength after wire-induced immobilization for 14 days. The expression of muscle atrophic factors (Atrogin1 and MuRF1) and inflammatory factors (F4/80 and interleukin-6 (IL-6)) significantly increased (p < 0.001). Notably, muscular AR expression significantly decreased, whereas myostatin and CCAAT/enhancer-binding protein delta (C/EBPδ), a transcriptional activator of myostatin, were significantly elevated (p < 0.05). After castration, AR expression further decreased, and muscular changes with wire-induced immobilization deteriorated. These exacerbations were completely ameliorated by testosterone supplementation and AR upregulation. Our study provides important therapeutic insights into testosterone/AR in muscular atrophy caused by immobilization and shows that muscular AR in a testosterone-dependent manner regulates C/EBPδ/myostatin and inflammation.

Keywords:  Androgen receptor; Inflammation; Male; Myostatin; Sarcopenia; Testosterone

DOI:  https://doi.org/10.1038/s41598-025-95115-6
BMC Musculoskelet Disord. 2025 Mar 22. 26(1): 285

Bioinformatics and machine learning approaches to explore key biomarkers in muscle aging linked to adipogenesis.

Yumin Zhang, Li Qin, Juan Liu.

  Adipogenesis is intricately linked to the onset and progression of muscle aging; however, the relevant biomarkers remain unclear. This study sought to identify key genes associated with adipogenesis in the context of muscle aging. Firstly, gene expression profiles from biopsies of the vastus lateralis muscle in both young and elderly population were retrieved from the GEO database. After intersecting with the results of differential gene analysis, weighted gene co-expression network analysis, and sets of adipogenesis-related genes, 29 adipogenesis-related differential expressed genes (ARDEGs) were selected. Connectivity Map (cMAP) analysis identified tamsulosin, fraxidin, and alaproclate as key target compounds. In further, using three machine learning algorithms and the friends analysis, four hub ARDEGs, ESRRA, RXRG, GADD45A, and CEBPB were identified and verified in vivo aged mice muscles. Immune infiltration analysis showed a strong link between several immune cells and hub ARDEGs. In all, these findings suggested that ESRRA, RXRG, GADD45A, and CEBPB could serve as adipogenesis related biomarkers in muscle aging.

Keywords:  Adipogenesis; Bioinformatics; Feature gene; Immune cell infiltration; Machine learning; Muscle aging; WGCNA analysis

DOI:  https://doi.org/10.1186/s12891-025-08528-9
Cells. 2025 Mar 07. pii: 390. [Epub ahead of print]14(6):

Chloroquine Causes Aging-like Changes in Diaphragm Neuromuscular Junction Morphology in Mice.

Chloe I Gulbronson, Sepideh Jahanian, Heather M Gransee, Gary C Sieck, Carlos B Mantilla.

  Autophagy impairments have been implicated in various aging conditions. Previous studies in cervical motor neurons show an age-dependent increase in the key autophagy proteins LC3 and p62, reflecting autophagy impairment and autophagosome accumulation. Chloroquine is commonly used to inhibit autophagy by preventing autophagosome-lysosome fusion and may thus emulate the effects of aging on the neuromuscular system. Indeed, acute chloroquine administration in old mice decreases maximal transdiaphragmatic pressure generation, consistent with aging effects. We hypothesized that chloroquine alters diaphragm muscle neuromuscular junction (NMJ) morphology and increases denervation. Adult male and female C57BL/6 × 129J mice between 5 and 8 months of age were used to examine diaphragm muscle NMJ morphology and denervation following daily intraperitoneal injections of chloroquine (10 mg/kg/d) or vehicle for 7 days. The motor end-plates and pre-synaptic terminals were fluorescently labeled with α-bungarotoxin and anti-synaptophysin, respectively. Confocal microscopy was used to assess pre- and post-synaptic morphology and denervation. At diaphragm NMJs, chloroquine treatment decreased pre-synaptic volume by 12% compared to the vehicle (p < 0.05), with no change in post-synaptic volume. Chloroquine treatment increased the proportion of partially denervated NMJs by 2.7-fold compared to vehicle treatment (p < 0.05). The morphological changes observed were similar to those previously reported in the diaphragm muscles of 18-month-old mice. These findings highlight the importance of autophagy in the maintenance of the structural properties at adult NMJs in vivo.

Keywords:  autophagy; diaphragm muscle; motor end-plate; neuromuscular junction; pre-synaptic terminal

DOI:  https://doi.org/10.3390/cells14060390