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Skeletal Muscle Function and Metabolism: Molecular Mechanisms and Treatment—2nd Edition

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A Special Issue of International Journal of Molecular Sciences (ISSN 1422-0067) belonging to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 May 2026) | Viewed by 30678

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Dr. Andrea Telek

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Department of Physiology, University of Debrecen, Debrecen, Hungary
Interests: skeletal muscle
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Special Issue Information

Dear Colleagues,

This Special Issue will focus on the most recent findings on molecular advances in skeletal muscle function. Despite recent improvements in this field, important information is still missing regarding skeletal muscle metabolism. Mitochondria serve as the final targets of metabolism-related signalization pathways, and their dynamic nature requires precise regulatory mechanisms. A final response could be modified by epigenetic mechanisms, including the inhibition of protein translation by miRNA and other forms of gene expression regulation. Since skeletal muscle is involved in lipid and glucose homeostasis, it can serve as a target in the treatment of metabolic disorders. Additionally, understanding the molecular background of disorders primarily affecting skeletal muscle could improve therapeutic options in dystrophies, age-related muscle atrophy, and sarcopenia. In summary, further research is needed in order to completely understand the molecular regulation of skeletal muscle function. Therefore, we kindly invite you to publish your results in this Special Issue of IJMS entitled “Skeletal Muscle Function and Metabolism: Molecular Mechanisms and Treatment”. Submissions of original research papers and reviews are encouraged.

Dr. Andrea Telek
Guest Editor

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Keywords

skeletal muscle
metabolism
mitochondria
epigenetics
exercise
signalization

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Skeletal Muscle Function and Metabolism: Molecular Mechanisms and Treatment in International Journal of Molecular Sciences (13 articles)

Published Papers (9 papers)

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Research

Jump to: Review, Other

29 pages, 1996 KB

Open AccessArticle

Activation of ATP Consumption Is Necessary to Stimulate Glycogenolysis in Skeletal Muscle

by Michael V. Martinov, Svetlana I. Sudarkina, Fazoil I. Ataullakhanov and Victor M. Vitvitsky

Int. J. Mol. Sci. 2026, 27(16), 7106; https://doi.org/10.3390/ijms27167106 - 8 Aug 2026

Viewed by 681

Abstract

Glycogenolysis is an important contributor to ATP production in contracting skeletal muscle. However, the activation of glycogen phosphorylase in resting muscle does not by itself trigger significant glycogenolysis. To elucidate the mechanisms underlying this regulation, we analyzed the functional coupling between glycogenolysis and glycolysis using a mathematical model of energy metabolism in mammalian fast-twitch (white) skeletal muscle. A system-level analysis of the model reveals an important role for inorganic phosphate (a substrate for glycogen phosphorylase) in regulating glycogenolysis rates in both resting and contracting muscle. In contracting muscle, at sufficiently high concentrations of inorganic phosphate, the activation of glycogen phosphorylase markedly increases the rate of glycogenolysis, thereby enhancing ATP production and stabilizing the cellular energy charge. In contrast, glycogen phosphorylase activation in resting muscle is unable to support glycogen breakdown due to a significant decrease in inorganic phosphate levels. Moreover, the analysis shows that forced acceleration of the glycogen phosphorylase reaction under resting conditions does not increase ATP production; instead, it promotes the accumulation of phosphorylated glycolytic intermediates, which may induce osmotic stress and cause damage to muscle cells. Full article

(This article belongs to the Special Issue Skeletal Muscle Function and Metabolism: Molecular Mechanisms and Treatment—2nd Edition)

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15 pages, 1841 KB

Open AccessArticle

Impact of Mutations in the NCAPG and MSTN Genes on Body Composition, Structural Properties of Skeletal Muscle, Its Fatty Acid Composition, and Meat Quality of Bulls from a Charolais × Holstein F₂ Cross

by Elke Albrecht, Praveen Krishna Chitneedi, Dirk Dannenberger, Christa Kühn and Steffen Maak

Int. J. Mol. Sci. 2026, 27(2), 882; https://doi.org/10.3390/ijms27020882 - 15 Jan 2026

Viewed by 1217

Abstract

Cattle breeds are optimized either for milk or meat production and secrete consumed nutrients in the form of milk or accrete nutrients as skeletal muscle tissue, respectively. Surplus energy is usually stored in the form of fat in adipose tissues. To gain more insight into the physiological and genetic background of nutrient accretion as either protein or fat, an experimental F₂ population was generated crossing Charolais (CH) bulls and German Holstein (GH) cows. Mutations in two genes with known, profound effects on growth were segregating in this population: the I442M mutation in the non-SMC condensin I complex, subunit G (NCAPG) gene, and the Q204X mutation in the myostatin (MSTN) gene. The major aim of this study was to close the gap between the described effects of the NCAPG/LCORL region and MSTN SNPs on carcass and meat quality traits, as well as on the structure and composition of the underlying tissues. Whole carcass data, meat quality traits, composition of major cuts and their dominating muscles, including muscle and fat cell structure, were analyzed as well as chemical and fatty acid composition. Mutant alleles of both loci were associated with higher weights, increased muscularity, and reduced fatness, e.g., each explaining about 15% of the observed variance. However, both loci apparently affect traits in a specific manner, influencing either dimensional traits or mass accretion. Full article

(This article belongs to the Special Issue Skeletal Muscle Function and Metabolism: Molecular Mechanisms and Treatment—2nd Edition)

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29 pages, 4846 KB

Open AccessArticle

In Vitro Study on the Effects of Rhododendron mucronulatum Branch Extract, Taxifolin-3-O-Arabinopyranoside and Taxifolin on Muscle Loss and Muscle Atrophy in C2C12 Murine Skeletal Muscle Cells

by Hyun Seo Lee, Hyeon Du Jang, Tae Hee Kim, Da Hyeon An, Ye Eun Kwon, Eun Ji Kim, Jae In Jung, Sangil Min, Hee Kyu Kim, Kwang-Hyun Park, Heesung Woo and Sun Eun Choi

Int. J. Mol. Sci. 2026, 27(2), 570; https://doi.org/10.3390/ijms27020570 - 6 Jan 2026

Cited by 2 | Viewed by 1754

Abstract

Sarcopenia, an age-related muscle atrophy disease, is a major health concern in aging societies and is closely associated with severe chronic diseases. Its primary pathogenesis involves oxidative stress-induced apoptosis in muscle cells and an imbalance in protein metabolism. This study evaluated the potential of Rhododendron mucronulatum branch extract (RMB) and its major flavonoids, taxifolin-3-O-arabinopyranoside (Tax-G) and taxifolin (Tax-A), as natural therapeutic agents for sarcopenia. Phytochemical analyses were performed using TLC, HPLC, LC-MS/MS, and NMR, and Tax-G and Tax-A were isolated from RMB. In vitro models of apoptosis and muscle atrophy were established in C2C12 cells using H₂O₂ and dexamethasone (DEX), respectively. Cell viability, myotube diameter, and protein expression related to apoptosis and muscle differentiation were assessed. All three substances reduced H₂O₂-induced apoptosis by increasing Bcl-2 and inhibiting cleaved caspase-3 and PARP. They also attenuated DEX-induced muscle atrophy by suppressing Atrogin-1, MuRF1, and FoxO3α while promoting MyoD, Myogenin, Akt, and mTOR. Although Tax-A showed the highest activity, Tax-G exhibited comparable effects with lower cytotoxicity. These findings demonstrate that RMB and its active compounds protect muscle cells by regulating apoptosis and muscle metabolism, suggesting their potential as safe and functional natural materials for the prevention of sarcopenia. Full article

(This article belongs to the Special Issue Skeletal Muscle Function and Metabolism: Molecular Mechanisms and Treatment—2nd Edition)

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13 pages, 2934 KB

Open AccessArticle

TAS1R3 Regulates GTPase Signaling in Human Skeletal Muscle Cells for Glucose Uptake

by Joseph M. Hoolachan, Rekha Balakrishnan, Karla E. Merz, Debbie C. Thurmond and Rajakrishnan Veluthakal

Int. J. Mol. Sci. 2026, 27(1), 103; https://doi.org/10.3390/ijms27010103 - 22 Dec 2025

Cited by 2 | Viewed by 1559

Abstract

Taste receptor type 1 member 3 (TAS1R3) is a class C G protein-coupled receptor (GPCR) traditionally associated with taste perception. While its role in insulin secretion is established, its contribution to skeletal muscle glucose uptake, a process responsible for 70–80% of postprandial glucose disposal, remains unclear. TAS1R3 expression was assessed in skeletal muscle biopsies from non-diabetic and type 2 diabetes (T2D) donors using qPCR and immunoblotting. Functional studies in human LHCN-M2 myotubes involved TAS1R3 inhibition with lactisole or siRNA-mediated knockdown, followed by the measurement of insulin-stimulated glucose uptake using radiolabeled glucose assays. Rac1 activation and phospho-cofilin were analyzed by G-LISA and Western blotting, and Gαq/11 involvement was tested using YM-254890. TAS1R3 mRNA and protein levels were significantly reduced in T2D skeletal muscle. Pharmacological inhibition or the knockdown of TAS1R3 impaired insulin-stimulated glucose uptake in myotubes. TAS1R3 regulates skeletal muscle glucose uptake through a non-canonical insulin signaling pathway involving Rac1 and phospho-cofilin, independent of IRS1-AKT and Gαq/11 signaling. These findings identify TAS1R3 as a key determinant of Rac1-mediated glucose uptake and a potential therapeutic target for improving insulin sensitivity in T2D. Full article

(This article belongs to the Special Issue Skeletal Muscle Function and Metabolism: Molecular Mechanisms and Treatment—2nd Edition)

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22 pages, 7324 KB

Open AccessArticle

In Vitro and In Vivo Comparative Analysis of Muscle Regenerative Processes Induced by Different Microcurrent Waveforms in Skeletal Muscle Atrophy

by Yoon-Jin Lee, Eun Sang Kwon, Yong Suk Moon and Dong Rak Kwon

Int. J. Mol. Sci. 2025, 26(19), 9333; https://doi.org/10.3390/ijms26199333 - 24 Sep 2025

Cited by 2 | Viewed by 1670

Abstract

This study aimed to evaluate the regenerative effects of various microcurrent waveforms in cast-induced gastrocnemius muscle atrophy in rabbits, integrating both in vitro and in vivo analyses. After two weeks of enforced hindlimb immobilization via casting, twenty-four rabbits were divided into four groups and treated for two weeks: Group-1 (control) received sham microcurrent, Group-2 was treated with a square waveform microcurrent, Group-3 with a sine waveform, and Group-4 with a triangular waveform. Treatments were administered daily for one hour. Calf circumference, muscle thickness (via ultrasound), tibial nerve CMAP, muscle fiber CSA, and protein expression (via Western blot analysis) were assessed. Among the groups, the sine waveform microcurrent resulted in significantly enhanced recovery across all measured parameters (p < 0.05), showing superior improvements in muscle thickness, CMAP amplitude, and fiber CSA. Immunohistochemical analysis revealed increased expression of proliferation and angiogenesis markers, including BrdU, PCNA, VEGF, and PECAM-1, while Western blotting demonstrated robust upregulation of myogenic regulatory factors such as MyoD and myogenin. Furthermore, levels of inflammatory and apoptotic markers, including TNF-α, NF-κB, and cleaved caspase-3, and stress response proteins, including p-CHK1 and p-CHK2, were markedly reduced. Collectively, these findings indicate that sine waveform microcurrent stimulation most effectively promotes muscle regeneration in both dexamethasone-induced C2C12 myoblasts and cast-induced muscle atrophy, underscoring its therapeutic potential and warranting further studies to optimize clinical application parameters. Full article

(This article belongs to the Special Issue Skeletal Muscle Function and Metabolism: Molecular Mechanisms and Treatment—2nd Edition)

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20 pages, 3972 KB

Open AccessArticle

Myotube Formation and Cellular Fusion Are Diminished Due to Low Birth Weight in Piglets

by Katja Stange and Monika Röntgen

Int. J. Mol. Sci. 2025, 26(7), 2847; https://doi.org/10.3390/ijms26072847 - 21 Mar 2025

Cited by 2 | Viewed by 1979

Abstract

Low birth weight (LBW) in various species leads to a pronounced skeletal muscle phenotype and can serve as a model to study muscle formation and draw conclusions for normal and pathological development. We aimed to elucidate in detail how the differentiation of muscular stem cells and their progeny are disturbed in piglets born with LBW. We isolated primary muscle cells from LBW piglets and their normal siblings with two different approaches: (1) single cells from two functionally divergent subpopulations (previously named “fast” and “slow”) and (2) cells derived from isolated, intact myofibers. Subsequently, we analyzed their proliferative and differentiative capacity by determining proliferation rate, migration behavior, myotube formation, and myogenic gene and protein expression. LBW led to a decreased proliferation rate and migration potential in cells from the subpopulation fast group. Cells from LBW piglets were generally able to differentiate, but they formed smaller myotubes with less incorporated nuclei, leading to a diminished fusion rate. Myogenic gene expression was also significantly altered due to pig birth weight. Overall, early postnatal muscle development in LBW was disturbed at several crucial steps involving the establishment of a reserve stem cell pool, movement of cells towards existing myofibers, and the ability to form nascent myofibers. Full article

(This article belongs to the Special Issue Skeletal Muscle Function and Metabolism: Molecular Mechanisms and Treatment—2nd Edition)

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Review

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16 pages, 1247 KB

Open AccessReview

When Bone Forms Where It Shouldn’t: Heterotopic Ossification in Muscle Injury and Disease

by Anthony Facchin, Sophie Lemaire, Li Gang Toner, Anteneh Argaw and Jérôme Frenette

Int. J. Mol. Sci. 2025, 26(15), 7516; https://doi.org/10.3390/ijms26157516 - 4 Aug 2025

Cited by 10 | Viewed by 4872

Abstract

Heterotopic ossification (HO) refers to the pathological formation of bone in soft tissues, typically following trauma, surgical procedures, or as a result of genetic disorders. Notably, injuries to the central nervous system significantly increase the risk of HO, a condition referred to as neurogenic HO (NHO). This review outlines the cellular and molecular mechanisms driving HO, focusing on the inflammatory response, progenitor cell reprogramming, and current treatment strategies. HO is primarily fuelled by a prolonged and dysregulated inflammatory response, characterized by sustained expression of osteoinductive cytokines secreted by M1 macrophages. These cytokines promote the aberrant differentiation of fibro-adipogenic progenitor cells (FAPs) into osteoblasts, leading to ectopic mineralization. Additional factors such as hypoxia, BMP signalling, and mechanotransduction pathways further contribute to extracellular matrix (ECM) remodelling and osteogenic reprogramming of FAPs. In the context of NHO, neuroendocrine mediators enhance ectopic bone formation by influencing both local inflammation and progenitor cell fate decisions. Current treatment options such as nonsteroidal anti-inflammatory drugs (NSAIDs), radiation therapy, and surgical excision offer limited efficacy and are associated with significant risks. Novel therapeutic strategies targeting inflammation, neuropeptide signalling, and calcium metabolism may offer more effective approaches to preventing or mitigating HO progression. Full article

(This article belongs to the Special Issue Skeletal Muscle Function and Metabolism: Molecular Mechanisms and Treatment—2nd Edition)

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Other

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10 pages, 2165 KB

Open AccessBrief Report

Skeletal Muscle Alterations in Different Phenotypes of Heart Failure with Preserved Ejection Fraction

by Beatrice Vahle, Romy Klädtke, Antje Schauer, T. Scott Bowen, Ulrik Wisløff, Axel Linke and Volker Adams

Int. J. Mol. Sci. 2025, 26(13), 6196; https://doi.org/10.3390/ijms26136196 - 27 Jun 2025

Cited by 2 | Viewed by 2497

Abstract

Heart failure with preserved ejection fraction (HFpEF) shows diverse disease patterns, with various combinations of comorbidities and symptoms. A common hallmark is exercise intolerance, caused by alterations in the peripheral skeletal muscle (SKM) including a recently indicated titin hyperphosphorylation. Our aim is to compare a metabolic syndrome- (ZSF-1 rats) and a hypertension-driven (Dahl salt-sensitive (DSS) rats) HFpEF rat-model in relation to SKM function and titin phosphorylation. Obese ZSF-1 and high-salt fed DSS rats (HFpEF) were compared to lean ZSF-1 and low-salt fed rats (con). HFpEF was confirmed by echocardiography and invasive haemodynamic measurements. SKM atrophy, in vitro force measurements, titin- and contractile protein expression were evaluated. Obese ZSF-1 HFpEF rats showed muscle atrophy, reduced muscle force and increased titin phosphorylation compared to controls, which was not detected in hypertensive DSS rats. Fiber type specific troponins, myostatin and four and a half LIM domain 1 were differently regulated between the two models. Altogether, our results show that both animal models of HFpEF exhibit different SKM phenotypes, probably based on the divergent disease etiologies, which may help to define the most suitable animal model for HFpEF to test potential treatment regimens. Full article

(This article belongs to the Special Issue Skeletal Muscle Function and Metabolism: Molecular Mechanisms and Treatment—2nd Edition)

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17 pages, 1097 KB

Open AccessOpinion

Delayed-Onset Muscle Soreness Begins with a Transient Neural Switch

by Balázs Sonkodi

Int. J. Mol. Sci. 2025, 26(5), 2319; https://doi.org/10.3390/ijms26052319 - 5 Mar 2025

Cited by 9 | Viewed by 13427

Abstract

Unaccustomed and/or strenuous eccentric contractions are known to cause delayed-onset muscle soreness. In spite of this fact, their exact cause and mechanism have been unknown for more than 120 years. The exploration of the diverse functionality of the Piezo2 ion channel, as the principal proprioceptive component, and its autonomously acquired channelopathy may bring light to this apparently simple but mysterious pain condition. Correspondingly, the neurocentric non-contact acute compression axonopathy theory of delayed-onset muscle soreness suggests two damage phases affecting two muscle compartments, including the intrafusal (within the muscle spindle) and the extrafusal (outside the muscle spindle) ones. The secondary damage phase in the extrafusal muscle space is relatively well explored. However, the suggested primary damage phase within the muscle spindle is far from being entirely known. The current manuscript describes how the proposed autonomously acquired Piezo2 channelopathy-induced primary damage could be the initiating transient neural switch in the unfolding of delayed-onset muscle soreness. This primary damage results in a transient proprioceptive neural switch and in a switch from quantum mechanical free energy-stimulated ultrafast proton-coupled signaling to rapid glutamate-based signaling along the muscle–brain axis. In addition, it induces a transient metabolic switch or, even more importantly, an energy generation switch in Type Ia proprioceptive terminals that eventually leads to a transient glutaminolysis deficit and mitochondrial deficiency, not to mention a force generation switch. In summary, the primary damage or switch is likely an inward unidirectional proton pathway reversal between Piezo2 and its auxiliary ligands, leading to acquired Piezo2 channelopathy. Full article

(This article belongs to the Special Issue Skeletal Muscle Function and Metabolism: Molecular Mechanisms and Treatment—2nd Edition)

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