bims-moremu 2026-10-25 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2026–10–25
28 papers selected by
Anna Vainshtein, Craft Science Inc.

Emerging roles of OSM and EDA2R-NIK signalling in cancer-associated muscle wasting.
Miro1 mediates skeletal muscle insulin resistance in type 2 diabetes.
Emerging evidence suggests that circadian disruption and muscle wasting form a self-reinforcing loop.
Timing the effort: Chronobiological drivers of skeletal muscle adaptation and metabolic health.
Exercise training does not mitigate high-phosphate diet-induced mitochondrial dysfunction in skeletal muscle in male mice.
Exercise training and mitochondrial remodeling in aging skeletal muscle: A translational systematic review and meta-analysis.
SH3BP2 deficiency in skeletal muscle leads to neuromuscular junction abnormalities and decreased muscle strength.
Dynamic increases in p53 expression suppress human myoblast differentiation.
Cellular Senescence in Skeletal Muscle: Molecular Mechanisms, Physiological Consequences, and Therapeutic Opportunities.
Physiological temperature attenuates fibre-type differences in human single-fibre contractile mechanics during isometric contractions.
Skeletal muscle transcriptomic profile of older adults with high-impact musculoskeletal pain in the study of muscle, mobility and aging (SOMMA).
Skeletal muscle fatigue resistance is differentially affected in 8-month-old male and female hAβ-KI mice.
Integrated Single-Myofibre Multi-Omics Correlates Inflammatory State to Myosin Energetics in ICU-Acquired Weakness.
HAMA microneedles patch loaded with muscle-targeting engineered apoptotic vesicles and attenuating sarcopenia by regulating mitochondrial homeostasis.
Targeting Muscle-Specific E3 Ligases in Cancer Cachexia Through Structure-Based Virtual Screening of Small-Molecule Inhibitors.
Diabetic Polyneuropathy Patients Exhibit an Altered Skeletal Muscle Proteome Phenotype.
Computational identification of candidate biomarkers and compounds associated with skeletal muscle insulin sensitivity improvement mediated by physical activity: an integrative multi-omics and computational chemistry study.
Skeletal muscle is a critical site of disrupted lipid metabolism in male hypogonadism: an in vivo interventional study.
The pyrin inflammasome senses OCTN2-mediated uptake of extracellular ʟ-carnitine from muscle injury or ingestion.
Effects of GLP-1 medications on skeletal muscle and exercise as a countermeasure.
Laminin-α2 deficiency is associated with altered multiorgan redox signatures.
Human serum collected after fermented whey protein supplementation stimulates myocellular growth and protein synthesis: A randomized, double-blind, active-controlled crossover trial.
Contractile function and insulin sensitivity are inversely regulated by insulin in primary myoblast human skeletal muscle microtissues.
Spheroid-based generation of 3D myogenic tissues using transgene- and sorting-free differentiation of hiPSCs.
SMCHD1 loss rewires MYOD1 enhancer nexuses and chromatin accessibility landscapes in muscle cells.
Spatiotemporal metabolic networks in a preclinical model of pancreatic cancer and associated cachexia.
Association between the ACTN3 R577X polymorphism and skeletal muscle mass: a systematic review and meta-analysis.
Glucose-Lowering Therapies in Type 2 Diabetes-Associated Sarcopenia: Mechanisms, Clinical Evidence and a Muscle-Centred Framework.

J Muscle Res Cell Motil. 2026 Oct 17. pii: 23. [Epub ahead of print]47(4):

Emerging roles of OSM and EDA2R-NIK signalling in cancer-associated muscle wasting.

Zuleyha Yildirim, Aleyna Kizilyer, Serkan Kir.

  Cancer-associated cachexia (CAC) is a multifactorial metabolic syndrome characterized by progressive skeletal muscle wasting that reduces physical function, compromises treatment tolerance, and contributes to cancer-related mortality. Although systemic inflammation is a major driver of CAC, the mechanisms through which circulating inflammatory signals are translated into muscle-specific catabolic programmes remain incompletely understood. Recent studies have identified oncostatin M (OSM), a member of the IL-6 cytokine family, as an important mediator of cancer-induced muscle wasting through OSM/JAK/STAT3 signalling. OSM also induces the expression of ectodysplasin A2 receptor (EDA2R) in skeletal muscle, which engages NF-κB-inducing kinase (NIK)-dependent non-canonical NF-κB signalling to promote atrophy-related gene expression, proteolysis, and metabolic dysfunction. Beyond CAC, the emerging association of EDA2R with aging, muscle-wasting disorders, and circulating disease signatures highlights its broader biological and translational relevance. In this review, we discuss recent advances in the understanding of mechanisms underlying skeletal muscle wasting linked to CAC. Specifically, we focus on OSM/JAK/STAT3 and EDA2R-NIK signalling and explore their potential implications for targeted therapeutic strategies.

Keywords:  Cancer-associated cachexia; EDA2R; NF-κB signalling; NIK; Oncostatin M; Skeletal muscle wasting

DOI:  https://doi.org/10.1007/s10974-026-09741-2
Nat Commun. 2026 10 19. pii: 10702. [Epub ahead of print]17(1):

Miro1 mediates skeletal muscle insulin resistance in type 2 diabetes.

Elizabeth C Heintz, Wagner S Dantas, Analisa L Taylor, Elizabeth R M Zunica, Kathryn P Belmont, Jackson M Slone, Jacob T Mey, Robbie Beyl, Bolormaa Vandanmagsar, Hailey A Parry, Peter Ajayi, Brian Glancy, Christopher L Axelrod, John P Kirwan.

Imbalanced skeletal muscle mitochondrial dynamics contribute to the onset and progression of type 2 diabetes (T2D) by mechanisms that remain incompletely understood. Here, we examined the role of Mitochondrial Rho GTPase 1 (Miro1), an outer mitochondrial membrane enzyme, in regulating skeletal muscle insulin action and glucose homeostasis in type 2 diabetes (T2D). In a cross-sectional clinical study, we show that Miro1 accumulates in the skeletal muscle of patients with obesity and T2D, which was further replicated in mouse models of T2D. This accumulation is explained by inadequate insulin-mediated interaction between AKT and Miro1 at the outer mitochondrial membrane. In a randomized controlled trial (NCT02977442), we show that exercise training relieves skeletal muscle Miro1 accumulation while improving insulin sensitivity in patients with T2D. Muscle-specific Miro1 deletion improves oxidative capacity and insulin sensitivity in mice and cells. Taken together, these data support a key regulatory role for skeletal muscle Miro1 in the pathophysiology of T2D. ClinicalTrials.gov Identifier: NCT02977442.

DOI: https://doi.org/10.1038/s41467-026-77278-6
Chronobiol Int. 2026 Oct 17. 1-9

Emerging evidence suggests that circadian disruption and muscle wasting form a self-reinforcing loop.

Feifei Li, Chunhong Liu.

  Circadian disruption and skeletal muscle wasting frequently co-occur in critical illness, shift work, and aging. We propose a bidirectional self-reinforcing loop in which each process amplifies the other. Environmental disruption of the skeletal muscle clock impairs protein turnover and mitochondrial function, triggering atrophy. The resulting loss of muscle mass weakens peripheral clock output and disrupts systemic circadian rhythms. The forward arm is supported by genetic evidence, particularly from global Bmal1 knockout models and human sleep-deprivation studies. The reverse arm is supported by correlative evidence from clinical observations and disease models. Chronotherapeutic interventions targeting this loop have shown preclinical efficacy and warrant clinical translation.

Keywords:  Circadian clock; chronotherapy; self-reinforcing loop; skeletal muscle atrophy

DOI:  https://doi.org/10.1080/07420528.2026.2743668
Chronobiol Int. 2026 Oct 19. 1-20

Timing the effort: Chronobiological drivers of skeletal muscle adaptation and metabolic health.

Emrah Aykora, Gülfem Erbil, Damla Aykora.

  Exercise acts as a non-photic zeitgeber, resetting skeletal muscle circadian clocks that regulate metabolism, mitochondrial function, and insulin sensitivity. This review synthesizes current evidence on how exercise timing modulates skeletal muscle clock function and metabolic adaptation, with emphasis on divergent molecular pathways, sex-specific regulation, chrono-nutrition, and emerging evidence on immune-circadian interactions, myokine-mediated muscle-organ communication, and cellular stress responses. Exercise performed at different circadian phases activates distinct signaling networks despite identical mechanical workloads. Early active phase exercise, typically performed following an overnight fast, preferentially activates the AMPK-SIRT1-HIF1α axis, promoting lipid oxidation, metabolic stress sensing, and circadian phase advancement through PER/CRY modulation. Conversely, late phase exercise favors p38 MAPK-ATF2/CREB-PGC-1α signaling, enhancing mitochondrial biogenesis, oxidative phosphorylation, and Akt-AS160-GLUT4-mediated glucose disposal. Emerging evidence further suggests that circadian regulation of macrophage polarization, cGAS-STING signaling, contraction-induced myokine secretion, and proteostasis may contribute to time-dependent systemic adaptations, although direct human evidence remains limited. In addition, pronounced sexual dimorphism indicates that estrogen-mediated regulation of BMAL1/CLOCK signaling influences mitochondrial function and substrate selection. In conclusion, exercise timing represents an important regulator of metabolic health. Integrating circadian biology, nutritional timing, chronotype, sex, metabolic phenotype, and immune-metabolic context may facilitate the development of precision chrono-exercise strategies for metabolic and cardiometabolic disorders.

Keywords:  Circadian rhythm; chronobiology phenomena; clock genes; exercise; muscle; skeletal

DOI:  https://doi.org/10.1080/07420528.2026.2750361
Physiol Rep. 2026 Oct;14(20): e71139

Exercise training does not mitigate high-phosphate diet-induced mitochondrial dysfunction in skeletal muscle in male mice.

Hannah F Sanders, Dominic W Kolonay, Jade A Blackwell, Jiaru Liu, Isabella R Dobrski, Daniel A Branch, Lucas A Lefers, Benjamen H Kern, Kedryn K Baskin.

  Inorganic phosphate consumption in adults is two-to-three-fold higher than the recommended daily allowance due to its widespread use as a preservative and flavor enhancer in processed foods. We previously reported that 12 weeks of high-phosphate diet (HPD) reduced VO2max and altered metabolic gene expression and mitochondrial dysfunction in mouse skeletal muscle. Here, we investigated whether exercise training reverses the negative consequences of HPD. Male mice were fed normal (NPD) or HPD for 5 weeks, then continued on NPD or HPD with 9 weeks of voluntary exercise training. Serum, urine, and fecal phosphate increased within 1 day of HPD-feeding and remained elevated throughout the study. Trained NPD- and HPD-fed mice performed similarly on forced exercise tests, but mitochondrial respiration was significantly decreased in skeletal muscle from trained HPD-fed mice. RNA sequencing revealed distinct sets of differentially expressed genes when comparing sedentary versus exercise-trained muscle of HPD-fed mice relative to the same comparison in NPD-fed mice. These findings indicate that voluntary exercise training preserves endurance but does not fully restore gene expression or mitochondrial function in muscle from HPD-fed mice. Thus, HPD-induced skeletal muscle dysregulation is not completely reversible with exercise, underscoring the importance of both diet and exercise for metabolic health.

Keywords:  exercise; high‐phosphate diet; mitochondrial respiration; skeletal muscle metabolism

DOI:  https://doi.org/10.14814/phy2.71139
Arch Gerontol Geriatr. 2026 Sep 30. pii: S0167-4943(26)00304-3. [Epub ahead of print]152 106435

Exercise training and mitochondrial remodeling in aging skeletal muscle: A translational systematic review and meta-analysis.

Farhan Yousaf, Sean Kao, Shahid Ishaq, Iqbal Ali Shah, Shin-Da Lee.

  Aging skeletal muscle shows impaired mitochondrial function, altered redox regulation, disrupted fusion-fission balance, and reduced mitochondrial turnover. This translational systematic synthesis and meta-analysis evaluated whether exercise training remodels mitochondrial and functional outcomes in aging muscle. PubMed, EMBASE, and Web of Science were searched to June 26, 2026 following PRISMA 2020. Twenty-eight studies involving aged exercise groups compared to sedentary groups were included. Outcomes covered oxidative stress, mitochondrial dynamics, mitophagy, mitochondrial biogenesis/function, skeletal muscle morphology, and physiological performance. Random-effects meta-analysis showed a significant improvement in VO₂max/VO₂peak after exercise training (SMD = 0.46, p < 0.001; I² = 0%), whereas pooled changes in citrate synthase (SMD = 0.18, p = 0.450) and BMI (SMD = -0.09, p = 0.557) were not significant. The directional synthesis showed that mitochondrial biogenesis and function were consistently responsive across species, particularly for OXPHOS proteins, mitochondrial volume density, ATPmax, and SIRT1/SIRT3 signaling. Human and rodent studies assessed different, only partly overlapping mitophagy and mitochondrial dynamics markers. Therefore, differences in pathway responsiveness across species cannot be separated from differences in which markers were measured. Exercise training and lifelong physical activity were associated with changes in mitochondrial biogenesis, dynamics, mitophagy-related signaling, and muscle function in aging skeletal muscle. The observed patterns varied by training protocol and study design, but indirect comparisons and heterogeneous outcome measures preclude conclusions about the superiority of any modality. Human and rodent findings should therefore be interpreted as complementary evidence rather than equivalent estimates of biological response.

Keywords:  Aerobic exercise; Energy metabolism; Longevity; Sarcopenia

DOI:  https://doi.org/10.1016/j.archger.2026.106435
Front Mol Neurosci. 2026 ;19 1985823

SH3BP2 deficiency in skeletal muscle leads to neuromuscular junction abnormalities and decreased muscle strength.

Bhola Shankar Pradhan, Krzysztof M Bernadzki, Yauhen Bandaruk, Anna Siudzińska, Teresa De Cicco, Małgorzata Sotomska, Marta Gawor, Margareta Jabłońska, Joanna Krzemień, Grzegorz Chodaczek, Said Hashemolhosseini, Tomasz J Prószyński.

  Assembly and stabilization of a high density of acetylcholine receptors (AChRs) at the neuromuscular junction postsynaptic domain is fundamental for proper synaptic transmission. Here, we report the identification of a scaffold protein, SH3BP2, that exhibits polyvalent and direct interactions with the dystrophin-glycoprotein complex (DGC) and AChR pentamers. Loss-of-function experiments in cultured myotubes revealed that SH3BP2 promotes formation of AChR assemblies in muscle cells. Similarly, muscle-specific deletion of SH3BP2 in mice impairs AChR clustering during embryonic development and causes multiple neuromuscular junction morphological and ultrastructural abnormalities in adult animals. Mutant mice also exhibit defects in synaptic transmission, muscle strength, and general fitness. Our study identifies a novel role for SH3BP2 in modulating the neuromuscular junction in skeletal muscles.

Keywords:  AChR clustering; SH3BP2; acetylcholine receptors; dystrobrevin; neuromuscular junctions; skeletal muscle

DOI:  https://doi.org/10.3389/fnmol.2026.1985823
Front Cell Dev Biol. 2026 ;14 1844660

Dynamic increases in p53 expression suppress human myoblast differentiation.

Ingrid R Aragon, Neha Patole, Ajay Vachanaram, Avram Liban, Colin Hogendorn, Ulas Ozkurede, Feng Feng, Darko Bosnakovski, Eric Batchelor, Julia C Liu.

  Skeletal muscle maintenance and regeneration are highly regulated by cell fate decisions made by muscle stem cells and their progeny, myoblasts. Although the transcription factor p53 is well known for its role in cellular stress responses, cell cycle regulation, and tumor prevention, emerging evidence suggests that p53 also plays a critical role in determining whether myoblasts differentiate into muscle fibers or remain single cells that re-enter quiescence to replenish the satellite cell pool. Most previous studies, however, have relied on static, population-level measurements of p53, leaving its dynamic real-time behavior in individual myoblasts largely unexplored. In this study, we use single cell time-lapse microscopy to investigate temporal patterns of p53 activity in fluorescently-tagged immortalized human myoblasts induced to differentiate. We find that cells in which p53 levels increase more quickly and accumulate to higher amplitudes tend to remain single cells rather than differentiate and fuse into myofibers. Understanding how p53 dynamics influence muscle cell fate may provide fundamental insights into muscle maintenance, regeneration, and degenerative disease.

Keywords:  differentiation; dynamics; myoblast; p53; time-lapse fluorescence microscopy

DOI:  https://doi.org/10.3389/fcell.2026.1844660
Annu Rev Physiol. 2026 Oct 21.

Cellular Senescence in Skeletal Muscle: Molecular Mechanisms, Physiological Consequences, and Therapeutic Opportunities.

Rylee Kopchak, Nathan K LeBrasseur.

Cellular senescence is a stress-responsive cell fate characterized by stable growth arrest and acquisition of a proinflammatory senescence-associated secretory phenotype. Senescent cells accumulate with advancing age and contribute to dysfunction and disease across multiple organ systems. In skeletal muscle (SkM), emerging evidence indicates that senescence arises across diverse cell populations that collectively reshape the SkM niche. Through the SASP and altered intercellular signaling, senescent cells promote chronic inflammation, fibrosis, impaired regeneration, and metabolic dysfunction that contribute to SkM loss, SkM weakness, functional decline, and frailty. This review synthesizes current knowledge of the molecular drivers, hallmarks, and cellular origins of senescence within SkM and highlights the physiological consequences that extend from the cellular to the organismal level. We also discuss emerging senotherapeutic strategies that hold promise for optimizing SkM health and function with aging and disease.

DOI: https://doi.org/10.1146/annurev-physiol-040725-104324
J Physiol. 2026 Oct 22.

Physiological temperature attenuates fibre-type differences in human single-fibre contractile mechanics during isometric contractions.

Carlos S Zepeda, Laura E Teigen, Marta Colosio.



Keywords:  ageing; myosin heavy chain; skeletal muscle fibre; temperature

DOI:  https://doi.org/10.1113/JP292187
Mol Pain. 2026 Jan-Dec;22:22 17448069261499172

Skeletal muscle transcriptomic profile of older adults with high-impact musculoskeletal pain in the study of muscle, mobility and aging (SOMMA).

Javier A Tamargo, Yutao Zhang, Muhammad Abbas, Li Chen, Lauren M Sparks, Theresa Mau, Russell T Hepple, Karyn A Esser, Yenisel Cruz-Almeida.

  High-impact musculoskeletal pain (i.e., pain that limits daily activities and function) affects a substantial proportion of older adults and is associated with accelerated mobility decline. While skeletal muscle is central to movement and functional capacity, its molecular contribution to pain-related disability in aging remains poorly understood. We conducted a cross-sectional analysis of baseline data from 742 community-dwelling adults aged 70 years or older from the Study of Muscle, Mobility and Aging (SOMMA). Bulk RNA sequencing was performed on vastus lateralis muscle biopsies. Pain impact was classified using self-reported pain and limitations in activities of daily living. Differential gene expression was examined comparing high-impact pain, low-impact pain, and no pain, with sex-stratified analyses. Pathway enrichment analyses were conducted to identify biological processes associated with high-impact pain. High-impact musculoskeletal pain was associated with a distinct skeletal muscle transcriptomic profile, whereas minimal differences were observed between low-impact pain and no pain. Sex-stratified analyses revealed substantial differences in pain-related gene expression for men and women. In men, high-impact pain was characterized by enrichment of musculoskeletal structural and extracellular matrix pathways. In women, high-impact pain was associated with broader transcriptional alterations involving immune, inflammatory, metabolic, and cytoskeletal processes. High-impact musculoskeletal pain in older adults was associated with sex-dependent skeletal muscle transcriptomic signatures distinct from those observed in low-impact pain. These findings implicate muscle-specific molecular pathways in pain-related functional limitations and highlight the importance of sex-informed approaches to understanding and treating chronic pain in aging.

Keywords:  Chronic Pain; Gene Expression Profiling; Mobility Limitations; Older Adults; Sex Factors

DOI:  https://doi.org/10.1177/17448069261499172
Physiol Rep. 2026 Oct;14(20): e71153

Skeletal muscle fatigue resistance is differentially affected in 8-month-old male and female hAβ-KI mice.

Emily N Copeland, Evelin Melekh, Val Andrew Fajardo, Rebecca E K MacPherson.

  Approximately 95% of Alzheimer's disease (AD) diagnoses are sporadic onset, present after the age of 65, and arising from a combination of non-modifiable and modifiable factors. This underscores the potential to identify early systemic changes that may contribute to disease development. One factor may be skeletal muscle atrophy, which has been associated with cognitive decline, although the exact relationship between skeletal muscle and the brain is unknown. Furthermore, whether muscle atrophy begins prior to or after the onset of AD remains elusive. The humanized amyloid-beta knock-in mouse (hAβ-KI) exhibits age-related cognitive decline, insoluble Aβ accumulation, inflammation and microglial activation, making it a useful model of sporadic AD. However, characterization of skeletal muscle changes with aging has yet to be examined. Here, we assess skeletal muscle form and function of the hAβ-KI mouse at 8 and 15 months of age, before and after onset of cognitive decline, through assessment of whole-body lean mass percentage, isolated muscle contraction of the extensor digitorum longus (EDL) and soleus muscle, and fiber type analysis of male and female mice. Whole-body lean mass declined over time in all mice; however, only male hAβ-KI mice had a significant change in body mass and lean mass over the study. At 8-months-old, the isolated EDL of male hAβ-KI mice fatigued faster than the WT mice, but there were no differences at 15 months-old nor fiber type composition at either age. Alternatively, the isolated EDL and soleus of 8-month-old hAβ-KI female mice fatigued slower compared to the WT mice, and there were no differences at 15 months nor fiber type composition at either age. This preliminary characterization work suggests sex-dependent differences in isolated muscle fatigue prior to cognitive decline in the hAβ-KI mouse model of sporadic AD.

Keywords:  age; amyloid beta; mouse; sex; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.71153
J Cachexia Sarcopenia Muscle. 2026 Oct;17(5): e70407

Integrated Single-Myofibre Multi-Omics Correlates Inflammatory State to Myosin Energetics in ICU-Acquired Weakness.

Alexandra M Winant, Roger Moreno-Justicia, Lucia Paolini, Wout J Claassen, Coen A C Ottenheijm, Atul S Deshmukh, Stefano Cattaneo, Simone Piva, Nicola Latronico, Robert A E Seaborne, Julien Ochala.

   BACKGROUND: Skeletal muscle atrophy is a pervasive complication of critical illness that worsens survival and recovery, yet remains poorly explained by current clinical or molecular markers.
METHODS: To directly connect disease-associated molecular states to the contractile machinery, this study combined sequential functional, transcriptomic and proteomic profiling of the same single human skeletal myofibres from critically ill patients in the intensive care unit with acquired weakness (ICU-AW) and controls. This integrated approach provides a framework for validating molecular signals directly within the cellular and biomechanical context.
RESULTS: Differential expression analyses between control and ICU-AW myofibres show marked donor-level heterogeneity, with no differentially expressed features (FDR < 0.05). Ranked gene set enrichment analyses revealed distinct transcriptional and proteomic signatures between conditions, as well as a subtle yet conserved myofibre state enriched in ICU-AW, characterised by inflammatory and chemotactic gene programmes, intracellular structural remodelling and bioenergetic adaptation. Nineteen features were significantly (FDR < 0.05) altered at both RNA and protein levels from the same myofibre. Overall, these 19 overlapping features link an inflammatory transcriptional landscape to a proteomic shift toward mitochondrial and translational machinery, revealing a coordinated stress-adaptation programme with selective post-translational control in fibres from patients with ICU-AW. Further integration with the functional dataset revealed fibres in this state displayed selectively disrupted myosin dynamics, evidenced by prolonged ATP turnover time of myosin heads in their super-relaxed conformation, suggesting altered myosin energetics as a contributor to muscle dysfunction.
CONCLUSIONS: These findings define a discrete, disease-associated myofibre state and validate a proof-of-concept integrative single-fibre framework for connecting multi-omic heterogeneity to molecular motor function in complex human disease. The identification of coordinated transcriptomic and proteomic programmes, validated through functional measurement, suggests that targeting this fibre state may offer new therapeutic opportunities in ICU-acquired dysfunction and related muscle disorders.

Keywords:  critical illness; multi‐omics; muscle weakness; myosin energetics; single‐fibre analysis; skeletal muscle heterogeneity

DOI:  https://doi.org/10.1002/jcsm.70407
J Nanobiotechnology. 2026 Jul 24. pii: 969. [Epub ahead of print]24(1):

HAMA microneedles patch loaded with muscle-targeting engineered apoptotic vesicles and attenuating sarcopenia by regulating mitochondrial homeostasis.

Jiayao Zhang, Zhao Lin, Haiqi Ding, Mingjuan Zhang, Yibin Su, Linhai Yang, Dingqiang Chen, Xuanhao Chen, Jun Luo, Fuli Wen, Guoyu Yu, Zineng Yan, Jie Xu.

   BACKGROUND: Sarcopenia is an age-related disorder characterized by the progressive loss of skeletal muscle mass and function, primarily driven by mitochondrial dysfunction, oxidative stress, and impaired satellite cell activity. Conventional therapeutic strategies have shown limited efficacy in restoring muscle performance. Apoptotic vesicles (ApoVs) derived from mesenchymal stem cells (MSCs) have recently emerged as promising therapeutic agents capable of delivering bioactive cargos to regulate cellular metabolism and attenuate tissue aging. However, the targeted delivery and functional stability of ApoVs remain major challenges.
RESULTS: We engineered human umbilical cord MSC-derived ApoVs with the muscle-specific aptamer A01B and encapsulated them in a methacrylated hyaluronic acid (HAMA) hydrogel microneedle patch to enhance tissue targeting and enable sustained release. In vitro, ApoVs were efficiently internalized by C2C12 myotubes and alleviated dexamethasone-induced atrophy by promoting proliferation, reducing oxidative stress, restoring mitochondrial structure and function, and modulating the PTEN-PI3K-AKT signaling pathway. miRNA profiling identified miR-21-5p as a key ApoV-delivered effector that activates this pathway. In vivo, treatment with the aptamer-functionalized ApoV microneedle system significantly improved muscle mass, myofiber cross-sectional area, mitochondrial oxidative capacity, and functional endurance in sarcopenic mice compared with controls.
CONCLUSIONS: Our findings demonstrate that the muscle-targeted delivery of engineered ApoVs via HAMA microneedles effectively reverses key hallmarks of sarcopenia by restoring mitochondrial homeostasis and activating PI3K/AKT signaling through miR-21-5p. This microneedle-based ApoV platform provides a promising cell-free therapeutic strategy for ameliorating muscle atrophy and functional decline.

Keywords:  Apoptotic vesicles; Hydrogel microneedles; Mesenchymal stem cells; Mitochondria; Sarcopenia

DOI:  https://doi.org/10.1186/s12951-026-04813-4
MicroPubl Biol. 2026 ;2026

Targeting Muscle-Specific E3 Ligases in Cancer Cachexia Through Structure-Based Virtual Screening of Small-Molecule Inhibitors.

Irfana Muqbil, Jordan D Johnson.

Cachexia is a multifactorial metabolic syndrome characterized by severe skeletal muscle loss that cannot be reversed by nutritional support. Common in cancer and other chronic diseases, it significantly increases morbidity and mortality. Muscle wasting is primarily driven by activation of the ubiquitin-proteasome pathway through the E3 ubiquitin ligases MuRF1 and Atrogin-1, which promote protein degradation and muscle atrophy. This study used computational modeling and docking to identify small-molecule inhibitors targeting these ligases, including repurposed drugs with anti-cachectic potential. Thalidomide and EM12-So2F were prioritized based on integrated docking, binding affinity, and drug-likeness/ADME analyses for validation in C2C12 myotube-based cachexia models.

DOI: https://doi.org/10.17912/micropub.biology.002256
Proteomics Clin Appl. 2026 Nov;20(6): e70060

Diabetic Polyneuropathy Patients Exhibit an Altered Skeletal Muscle Proteome Phenotype.

Frederik Forsberg Thybo, Karolina Snopek Khan, Jesper Emil Jakobsgaard, Henning Andersen, Kristian Vissing, Johan Palmfeldt.

   PURPOSE: Diabetic polyneuropathy (DPN) is a debilitating complication of diabetes that affects motor nerves and may impair skeletal muscle health. This study investigated skeletal muscle proteomic alterations associated with DPN compared with type 2 diabetes without DPN (T2D) and healthy controls (CON).
EXPERIMENTAL DESIGN: An exploratory proteomic profiling was performed in 15 participants divided into three groups based on clinical and neurophysiological diagnosis (DPN, n = 5; T2D, n = 5; CON, n = 5). Biopsies from the gastrocnemius lateralis muscle were analyzed using LC-MS/MS-based proteomics and pathway enrichment analyses.
RESULTS: A total of 265 and 444 proteins were differentially expressed in DPN compared with T2D and CON, respectively (q < 0.05). Enrichment analyses revealed marked alterations in mitochondrial-related pathways, including cellular respiration, distinguishing DPN from both comparison groups. Differences between T2D and CON were present but less pronounced. DPN was characterized by downregulation of glycogen-regulating proteins (phosphorylase kinase G1 and A1) and upregulation of ferritin light chain (FTL), alpha actin 2, and myosin-binding protein H.
CONCLUSIONS AND CLINICAL RELEVANCE: DPN is associated with a distinct and progressive skeletal muscle proteomic phenotype, supporting mitochondrial dysfunction as a key feature and providing a basis for future mechanistic and therapeutic studies.

Keywords:  diabetes; diabetic polyneuropathy; mitochondria; muscle; proteomics

DOI:  https://doi.org/10.1002/prca.70060
Front Bioinform. 2026 ;6 1885995

Computational identification of candidate biomarkers and compounds associated with skeletal muscle insulin sensitivity improvement mediated by physical activity: an integrative multi-omics and computational chemistry study.

Hong Liu, Zicheng Liang, Jun Tan, Chunyun Yuan.

   Background: Insulin resistance (IR) underlies many chronic diseases. While physical activity improves skeletal muscle insulin sensitivity (IS), the underlying molecular mechanisms and targeted drug strategies remain elusive. This hypothesis-generating study integrates bioinformatics and computational chemistry using public datasets; all findings are computational predictions requiring experimental validation.
Methods: Using a skeletal muscle dataset (GSE24215, n = 10) of bed rest-induced IR and exercise-reversed IR, candidate genes were identified via WGCNA and differential expression analysis. Machine learning, GSEA, and regulatory network construction identified key targets and predicted mechanisms. To address the lack of targeted drugs, a deep learning-driven drug discovery and multi-scale binding validation strategy screened candidate compounds from natural and marine product databases.
Results: WNT4 was the only candidate gene repeatedly identified across both phases, displaying a bidirectional expression pattern of "upregulation after bed rest and downregulation after exercise retraining." GSEA predicts WNT4 expression is positively correlated with energy metabolism pathways (e.g., oxidative phosphorylation) and is mediated by predicted transcriptional (centered on EGR1) and post-transcriptional (hsa-miR-1238-3p/lncRNAs) regulatory networks. From over 700,000 screened compounds, three top candidates were identified. Molecular dynamics, binding free energy calculations, and quantum chemical analysis preliminarily predicted their binding stability and electronic structure features.
Conclusion: This study proposes that WNT4 may play a role in the dynamic regulation of skeletal muscle IS, presenting a functional hypothesis of "endogenous compensation-stage transition". It establishes a computational drug discovery pipeline providing a candidate compound library for WNT4. Given the limited sample size (n = 10), all findings require further validation in independent cohorts and experiments.

Keywords:  DFT; MM-GBSA; WNT4; deep learning; insulin sensitivity; molecular dynamics simulation; skeletal muscle

DOI:  https://doi.org/10.3389/fbinf.2026.1885995
J Clin Endocrinol Metab. 2026 Oct 22. pii: dgag432. [Epub ahead of print]

Skeletal muscle is a critical site of disrupted lipid metabolism in male hypogonadism: an in vivo interventional study.

Clare Miller, Leanne Cussen, Tara McDonnell, Marie McIlroy, Amar Agha, Catherine L Winder, Wanchang Lin, Warwick B Dunn, Jerome Coffey, Oleksandr Boychak, Brian O'Neill, Mark Sherlock, Michael W O'Reilly.

   CONTEXT: Male hypogonadism is associated with adverse cardiometabolic outcomes, however tissue-specific metabolic mechanisms underlying this phenotype remain poorly characterised. Metabolomic profiling in hypogonadism to date has been confined to plasma, with limited insights into skeletal muscle.
OBJECTIVE: To characterise the impact of testosterone replacement therapy (TRT) and androgen deprivation (ADT) on the plasma and skeletal muscle metabolome.
DESIGN: Parallel prospective interventional studies examined men initiating TRT for organic hypogonadism (n=15) and ADT for prostate cancer (n=15). Participants underwent metabolic phenotyping, plasma sampling and vastus lateralis muscle biopsies pre and post intervention (6 months TRT; 3 months ADT), with untargeted metabolomic profiling of both tissues at each timepoint.
RESULTS: TRT significantly increased serum testosterone (p<0.001) and muscle mass (p<0.05); ADT significantly reduced serum testosterone (p<0.001) and muscle mass (p<0.05) while simultaneously increasing fat mass (p<0.05). TRT significantly altered a total of 118 plasma metabolites, reflecting predominant suppression of circulating lipid species, whereas ADT altered only two. In skeletal muscle, TRT perturbed 89 metabolites and was characterised by expansion of intramuscular lipid species, while ADT altered 109 metabolites, with predominant depletion of intramuscular lipid classes. Following TRT, eight lipid classes showed divergent responses between plasma and skeletal muscle. In skeletal muscle, nine lipid classes responded differentially to TRT and ADT, including fatty acids, triacylglycerides and ceramides.
CONCLUSION: This study provides the first untargeted metabolomic characterisation of skeletal muscle in response to androgen manipulation in humans. Distinct plasma and skeletal muscle responses demonstrate tissue-specific regulation that is incompletely captured by plasma profiling alone. These findings highlight skeletal muscle as a key site of androgen-sensitive metabolic regulation, providing evidence for tissue-specific lipid partitioning that may contribute to the cardiometabolic consequences of hypogonadism.

Keywords:  Hypogonadism; androgen deprivation; skeletal muscle; untargeted metabolomics

DOI:  https://doi.org/10.1210/clinem/dgag432
Cell. 2026 Oct 19. pii: S0092-8674(26)01117-7. [Epub ahead of print]

The pyrin inflammasome senses OCTN2-mediated uptake of extracellular ʟ-carnitine from muscle injury or ingestion.

Eric I Elliott, Tomomi M Yoshida, Susana C B R Nakandakari, Scott Pope, Cuiling Zhang, Timothy Nottoli, Jae Jin Chae, Daniel L Kastner, Richard A Flavell, Vishwa Deep Dixit, Vijay A Rathinam, Fayyaz S Sutterwala, Andrew Wang.

  Red-meat-containing diets are epidemiologically associated with diseases of chronic inflammation, while diets that restrict red meat improve health. Yet, it is uncertain how red meat incites inflammation. Here, we discover that ʟ-carnitine, an amino acid highly concentrated in skeletal muscle myocytes, drives inflammasome activation in lipopolysaccharide (LPS)-challenged mice and LPS-primed murine and human macrophages. We find that extracellular ʟ-carnitine represses mevalonate synthesis, thereby triggering activation of the pyrin inflammasome, downstream of cellular import by the high-affinity ʟ-carnitine transporter OCTN2. We find that the inflammatory response to skeletal muscle injury also requires pyrin and OCTN2. Thus, in summary, we identify macrophages as sentinels of exogenous and endogenous extracellular ʟ-carnitine that serve as a proxy for skeletal myocyte damage, and we open the field to examine the mechanistic basis for how excess dietary intake of carnitine-rich food drives inflammatory disease.

Keywords:  ASC; MEFV; OCTN2; SLC22A5; caspase-1; inflammasome; interleukin-17a; interleukin-1β; pyrin; rhabdomyolysis; sepsis; ʟ-carnitine

DOI:  https://doi.org/10.1016/j.cell.2026.09.015
J Sport Health Sci. 2026 Oct 22. pii: S2095-2546(26)00076-1. [Epub ahead of print] 101185

Effects of GLP-1 medications on skeletal muscle and exercise as a countermeasure.

Paul Hendrickse, Junjie Xiao, T Scott Bowen.

DOI: https://doi.org/10.1016/j.jshs.2026.101185
Free Radic Biol Med. 2026 Oct 21. pii: S0891-5849(26)01233-5. [Epub ahead of print]257 697-712

Laminin-α2 deficiency is associated with altered multiorgan redox signatures.

Susana G Martins, Mafalda Pita, Sharadha Dayalan Naidu, Vanessa Ribeiro, Hebe Lameirão-Ferreira, Carlos Gravato, Albena T Dinkova-Kostova, Sólveig Thorsteinsdóttir, Ana Rita Carlos.

  Muscle diseases often involve redox imbalance, driven by elevated ROS levels, impaired antioxidant defenses, mitochondrial dysfunction, and metabolic rewiring. In several muscular dystrophies caused by extracellular matrix gene mutations, increased oxidative stress in skeletal muscle is a defining feature. One such condition is LAMA2-congenital muscular dystrophy (LAMA2-CMD), resulting from mutations in LAMA2, which encodes the laminin-α2 chain. Although oxidative stress has been implicated in the muscle pathology in LAMA2-CMD, whether this effect extends beyond skeletal muscle remains unclear. Here, we used the dyW mouse model for LAMA2-CMD, which exhibits well-established muscle defects beginning at fetal stages, to investigate whether pathology is also present in other organs at disease onset. We found that Lama2-deficiency alters antioxidant responses in the fetal heart, kidney, and liver, with all three organs displaying increased NRF2 protein levels accompanied by organ-specific changes in selected NRF2 target genes. This phenotype is associated with alterations in mitochondrial markers in the kidney, not evident in the heart or the liver. To further understand the kidney phenotype, we isolated Lama2-deficient proximal tubule epithelial cells from fetal kidneys, which displayed defects in proliferation and mitochondrial metabolism in vitro, indicating a cell-autonomous effect. However, alterations in the NRF2 pathway were not detected, suggesting that its regulation may depend on the in vivo tissue context. Overall, this study provides the first evidence supporting a multi-organ involvement in laminin-α2 chain deficiency from the earliest stages of disease, extending the known phenotype beyond skeletal muscle. It further underscores the importance of laminin-α2 chain in maintaining tissue homeostasis and redox balance, offering new insights into systemic aspects of LAMA2-CMD.

Keywords:  Heart; Kidney; LAMA2-congenital muscular dystrophy; Liver; Redox-associated changes

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.10.042
Exp Gerontol. 2026 Oct 23. pii: S0531-5565(26)00345-1. [Epub ahead of print] 113365

Human serum collected after fermented whey protein supplementation stimulates myocellular growth and protein synthesis: A randomized, double-blind, active-controlled crossover trial.

Kazuki Uemichi, Mito Watanabe, Naomi Yoshii, Kento Nozawa, Risako Mori, Shota Inoue, Yasushi Shinohara, Satoshi Fujita.

   BACKGROUND: Age-related anabolic resistance has been proposed as one contributor to skeletal muscle loss in older adults, although its magnitude varies substantially among individuals and experimental conditions. Whey protein stimulates muscle protein synthesis (MPS) through increased circulating amino acid availability and activation of mechanistic target of rapamycin complex 1 (mTORC1), whereas fermented whey protein may exert greater anabolic effects due to enhanced bioactivity. However, its effects on skeletal muscle anabolic and metabolic responses during aging remain unclear.
METHODS: This randomized, double-blind, placebo-controlled, crossover study investigated the effects of fermented whey protein ingestion on serum-mediated anabolic and metabolic responses in cultured skeletal muscle cells from young and older males. Participants consumed fermented whey protein (Fermentis) and conventional non-fermented protein (control whey) on separate occasions. Differentiated C2C12 myotubes were cultured in medium containing 10% postprandial human serum to evaluate MPS, mitochondrial-related signaling, and myotube hypertrophy.
RESULTS: Serum obtained after Fermentis ingestion increased myotube diameter compared with serum obtained after conventional whey protein, with no age × protein interaction. For MPS, we observed a significant age × protein interaction, and MPS was greater in myotubes treated with post-Fermentis serum from older donors than from young donors. In addition, serum obtained after Fermentis ingestion markedly enhanced S6K1 Thr389 phosphorylation and oxidative metabolism-related signaling molecules compared with non-fermented protein treatment.
CONCLUSIONS: The present findings may provide mechanistic insights into the development of nutritional strategies to attenuate age-associated anabolic resistance and improve skeletal muscle oxidative metabolic function.

Keywords:  Amino acids; Anabolic resistance; Muscle protein synthesis; Serum; Skeletal muscle cells; Whey protein

DOI:  https://doi.org/10.1016/j.exger.2026.113365
Biomed Eng Online. 2026 Jul 28. pii: 119. [Epub ahead of print]25(1):

Contractile function and insulin sensitivity are inversely regulated by insulin in primary myoblast human skeletal muscle microtissues.

Yekaterina Tiper, Jiaru Ni, Lucy Xinyu Ma, Cassidy T Tinline-Goodfellow, Paul Babits, Roman Krawetz, Daniel R Moore, Penney M Gilbert.

   BACKGROUND: Insulin resistance in skeletal muscle is a hallmark of Type 2 diabetes mellitus (T2D). Three-dimensional skeletal muscle microtissues (hMMTs) offer advantages over two-dimensional myotube cultures, including enhanced physiological relevance and amenability to repeated contractile stimulation. However, standard hMMT differentiation protocols rely on supraphysiological insulin concentrations. This creates a fundamental conundrum, since the very conditions required to generate functional hMMTs are expected to render them insulin-unresponsive, limiting their utility for modeling T2D. Whether hMMTs can be differentiated under more physiological conditions while maintaining myotube formation, contractile strength, and glucose transporter type 4 (GLUT4) expression and function, and whether insulin responsiveness can be restored post-differentiation, remains unknown.
METHODS: We systematically evaluated the effects of nutrient and insulin conditions on myotube morphometry, contractile function, and glucose transporter profiles (GLUT4, GLUT1, insulin receptor β) in human primary myoblast-derived 2D myotubes and hMMTs. We tested whether reducing insulin or glucose to physiological levels during differentiation impacted hMMT contractility. We then evaluated an insulin re-sensitization protocol involving insulin withdrawal to restore insulin responsiveness and assessed its impact on contractile function, glucose uptake, and AKT signaling.
RESULTS: Insulin supplementation during differentiation was essential for myonuclear accretion in 2D cultures and for contractile hMMT formation, with supraphysiological insulin (≥ 0.86 µM) levels required for maximal hMMT strength. Physiological glucose levels were sufficient to support myotube formation in 2D and 3D settings and even enhanced hMMT contractile force as compared to standard supraphysiological glucose formulations. hMMTs exhibited ~ 12-fold higher GLUT4 levels and a ~ 40-fold increase in GLUT4:GLUT1 ratio compared to 2D myotubes (p < 0.0001 and p = 0.044, respectively), approaching but not matching native adult human muscle. hMMTs differentiated in supraphysiological insulin appeared to display blunted insulin responsiveness. A 4-day insulin withdrawal period was associated with a partial restoration of insulin sensitivity, increasing insulin-stimulated glucose uptake ~ 1.5-fold and activating AKT signaling (N = 2). However, re-sensitization significantly compromised hMMT contractile strength (p < 0.0001) and fatigue resistance (p = 0.015).
CONCLUSION: We demonstrate that hMMTs derived from a 19-year-old female primary myoblast cell line require supraphysiological insulin during differentiation to achieve optimal contractile function and physiologically relevant GLUT4:GLUT1 ratios, but this renders them insulin-resistant. Although insulin withdrawal may partially restore insulin responsiveness, it impairs contractile integrity. These findings highlight a critical trade-off that may limit hMMT-based T2D modeling. Development of insulin-free differentiation protocols that preserve both contractile function and insulin sensitivity is important to unlock the potential of hMMTs for studying contraction-mediated therapeutic interventions in T2D.

Keywords:  Engineered skeletal muscle; Glucose transporter type 4; Type 2 diabetes

DOI:  https://doi.org/10.1186/s12938-026-01603-9
Biofabrication. 2026 Oct 20.

Spheroid-based generation of 3D myogenic tissues using transgene- and sorting-free differentiation of hiPSCs.

Jasper Smet, Dindi Remedios Tiamson Guzon, Rebecca Wüst, Brecht Bollaert, Lander Hauchecorne, Febe Boudry, Laura Yedigaryan, Maurilio Sampaolesi, Lieven Thorrez, Heidi Declercq.

   OBJECTIVE: Human induced pluripotent stem cells (hiPSCs) represent a clinically relevant cell source for skeletal muscle tissue engineering, yet transgene-free maturation remains challenging. Moreover, the potential of spheroids as building blocks for muscle engineering remains poorly defined. This study evaluated whether hiPSC-derived myogenic spheroids enhance biofabrication outcomes in an in vitro bio-artificial muscle (BAM) system compared to a conventional single cell approach.Methods. CD56+ hiPSC-derived myoblasts were generated using a transgene-free protocol and differentiated toward 2D myotubes. In 3D, myoblasts were aggregated into 140-200 µm spheroids. Spheroids or single cells were encapsulated in a fibrin-based BAM, kept under tension using metal pins. Non-encapsulated spheroids and BAMs were cultured up to 15 days and evaluated for myosin heavy chain (MYH)+ organization, transcriptional profile, and contractile function.Results. In 2D, MYH+ myotubes showing multinucleation and, occasionally, sarcomere striation were formed. Spheroids were successfully generated, increased in size and circularity, and showed an enhancing MYH positivity, particularly during the proliferation phase, and displayed a fetal/perinatal myogenic state. In BAMs, spheroids promoted MYH positivity and established larger continuous MYH+ structures. Transcriptional profiles of spheroid and single cell BAMs were broadly similar. Tetanic forces were generally higher in spheroid BAMs; however, this difference did not reach statistical significance.Conclusion. hiPSC-derived myogenic spheroids advance MYH expression, but terminal maturation is constrained, likely due to their intrinsically isotropic nature. Within BAMs, spheroids enhance MYH+ myotube formation, but do not overcome limitations in myoblast fusion. Incomplete spheroid outgrowth and poor control over their spatial distribution are important challenges for their integration. Future work should focus on improving hiPSC differentiation efficiency, implementing spheroids in earlier differentiation stages, and optimizing spheroid outgrowth and positioning, alongside incorporating remaining muscle components as fibroblasts and vascular cells. This will refine whether spheroid-based assembly can add value in specific biofabrication contexts. &#xD.

Keywords:  bio-artificial muscle; human induced pluripotent stem cells; skeletal muscle; spheroids; tissue engineering

DOI:  https://doi.org/10.1088/1758-5090/aeb6aa
Sci Adv. 2026 Oct 23. 12(43): eaeh7499

SMCHD1 loss rewires MYOD1 enhancer nexuses and chromatin accessibility landscapes in muscle cells.

Zhijun Huang, Wei Cui, Adam Klaiss, Gerd P Pfeifer.

SMCHD1 is a chromatin architectural protein linked to heterochromatin repression. Loss of function mutations of SMCHD1 cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) through activation of the DUX4 transcription factor gene. However, it is unknown how SMCHD1 may regulate transcription independently of DUX4. Here, we show that SMCHD1 safeguards enhancer organization within the three-dimensional (3D) genome in human myoblasts. Loss of SMCHD1 leads to widespread gains in chromatin accessibility, aberrant transcription, and selective remodeling of myogenic transcription factor MYOD1 occupancy. Integrative analyses of histone modifications, chromatin accessibility, Hi-C looping, and enhancer-gene modeling reveal that SMCHD1 loss rewires the landscape of clustered enhancers and promotes the emergence of new networks of enhancer elements, termed MYOD1 enhancer nexuses. These structures are marked by increased enhancer connectivity, increased local 3D chromatin interactions, and coordinated activation of genes likely relevant for FSHD pathology. Our findings identify SMCHD1 as a key architectural constraint that suppresses hyperactive enhancer networks, thereby preserving transcriptional homeostasis in myoblasts.

DOI: https://doi.org/10.1126/sciadv.aeh7499
Nat Commun. 2026 09 18. pii: 10949. [Epub ahead of print]17(1):

Spatiotemporal metabolic networks in a preclinical model of pancreatic cancer and associated cachexia.

Blanca Majem, Min-Sik Lee, Kyung Cheul Shin, Insia Naqvi, Courtney Dennis, Lucas Dailey, Sarah Jeanfavre, Mari Mino-Kenudson, Joao B Xavier, Clary B Clish, Deepti Mathur, Nada Y Kalaany.

Cachexia or body wasting is a significant contributing factor to the morbidity and mortality of pancreatic cancer. Despite an unmet need, its metabolic underpinnings remain poorly understood. Here, we characterize a mouse model that recaptures the longitudinal progression of human cachexia during pancreatic cancer development. We profile the metabolomes of pre-, early- and late-stage cancer-associated cachexia in male and female pancreas, its interstitial fluid (IF), plasma, liver, adipose tissue and skeletal muscle. We find that each tissue has a unique metabolome and trajectory across stages and reveal a marked lipid enrichment in the tumor IF. Using mathematical modeling, we identify metabolites participating in cross-tissue networks and in vivo validate a lactate-glucose conversion. We find systemic metabolic changes prior to weight loss and use feature selection algorithms to identify early detection markers. Our study provides a resource for system-wide metabolic evolution of pancreatic cancer and associated cachexia, highlighting the potential for timely diagnostics and interventions.

DOI: https://doi.org/10.1038/s41467-026-77745-0
J Physiol Anthropol. 2026 Jul 27. pii: 24. [Epub ahead of print]45(1):

Association between the ACTN3 R577X polymorphism and skeletal muscle mass: a systematic review and meta-analysis.

Sakura Hattori, Mika Kamiya-Saito, Naoki Kikuchi, Koichi Nakazato.

   BACKGROUND: The ACTN3 R577X polymorphism is one of the genetic factors influencing skeletal muscle mass. Although several studies have reported that the X allele of the ACTN3 R577X polymorphism is associated with reduced muscle mass, others have found no significant relationship between genotype and muscle mass. These inconsistencies may be explained by differences in background characteristics of the study populations, such as sex, age, ethnicity, and measurement site. This systematic review and meta-analysis aimed to clarify the association between the ACTN3 R577X polymorphism and skeletal muscle mass. In addition, we investigated whether the effect of the ACTN3 gene is modified by population background.
MAIN BODY: A total of 34 cohorts (9,496 participants) derived from 24 studies were included in the meta-analysis. In the overall analysis under the dominant model for the X allele (RR vs. RX + XX), the ACTN3 genotype showed a significant effect on skeletal muscle mass (SMD [95% CI] = - 0.08 [- 0.15 to - 0.02], p = 0.014), with the RX + XX group exhibiting lower skeletal muscle mass compared with the RR group. In contrast, the recessive model (RR + RX vs. XX) did not yield a statistically significant effect (SMD [95% CI] = - 0.02 [- 0.12 to 0.07], p = 0.616). Under the additive model, a trend toward an effect was observed (per-allele; β [95% CI] = - 0.05 [- 0.10 to 0.01], p = 0.078). Moderate heterogeneity was observed across all models (dominant: I2 = 38.8%; recessive: I2 = 55.8%; additive: I2 = 52.5%). No significant subgroup effects were observed for sex, age, or ethnicity. Meta-regression for measurement site indicated that the association became more pronounced as lower-limb specificity increased, although residual heterogeneity remained.
CONCLUSION: The ACTN3 R577X polymorphism showed a small association with skeletal muscle mass under the X-allele dominant model, suggesting that this association may be detectable even in heterozygous individuals. Although measurement site may modulate this association, none of the examined factors substantially explained the observed heterogeneity when considered individually. The remaining variability may reflect combinations of background characteristics that were not fully captured by single-factor analyses. Further studies accounting for background characteristics are warranted to clarify the genetic contribution of ACTN3 R577X to skeletal muscle mass.

Keywords:  ACTN3; ACTN3 R577X polymorphism; Sarcopenia; Skeletal muscle mass; α-actinin-3

DOI:  https://doi.org/10.1186/s40101-026-00439-5
Drugs. 2026 Oct 17.

Glucose-Lowering Therapies in Type 2 Diabetes-Associated Sarcopenia: Mechanisms, Clinical Evidence and a Muscle-Centred Framework.

Jing Zhang, Xiaodan Zhai, Sha Sha, Le Zhang.

Sarcopenia is increasingly recognised as a clinically important comorbidity in diabetes mellitus, particularly in older adults and individuals with long-standing type 2 diabetes. Because skeletal muscle is the principal site of insulin-stimulated glucose disposal, declines in muscle mass, quality, strength and physical performance may exacerbate insulin resistance and glycaemic instability and increase the risks of frailty, disability, falls, fractures, cardiovascular events and mortality. Contemporary glucose-lowering therapies have transformed diabetes care through established cardiorenal benefits and weight reduction, yet skeletal muscle outcomes are rarely prespecified or systematically assessed in pivotal trials. This evidence gap is especially relevant for weight-reducing agents such as glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, which are often associated with reductions in dual-energy X-ray absorptiometry-derived or bioelectrical impedance analysis-derived lean-mass estimates. However, these changes should be interpreted cautiously, as they often occur in the context of overall weight loss and may be influenced by alterations in body water. In addition, dual-energy X-ray absorptiometry- or dual-energy X-ray absorptiometry-derived lean-mass estimates do not directly quantify contractile skeletal muscle. Accordingly, reductions in lean-mass estimates alone are insufficient to infer clinically meaningful muscle loss without concurrent assessment of muscle strength or physical performance. This narrative review summarises the bidirectional mechanisms linking diabetes and sarcopenia and appraises major glucose-lowering drug classes from a muscle-centred perspective. It integrates mechanistic insights with human evidence on muscle-relevant outcomes, including body composition, strength and physical performance, and addresses practical safety and monitoring considerations in sarcopenia-prone phenotypes, including sarcopenic obesity. We also propose a pragmatic, hypothesis-generating Cardiorenal-Muscle Quadrant Framework that considers glycaemic efficacy and cardiorenal benefit alongside muscle reserve, functional status and treatment-related risks, with emphasis on functional monitoring, resistance exercise, nutritional optimisation and individualised glycaemic targets in older or frail adults.

DOI: https://doi.org/10.1007/s40265-026-02408-9