bims-moremu 2026-08-16 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2026–08–16
28 papers selected by
Anna Vainshtein, Craft Science Inc.

Temporal multi-omic analysis uncovers sex-biased molecular programs underlying skeletal muscle adaptation to endurance training.
Comprehensive transcriptomic profiling reveals impaired polyamine metabolism as a contributor to age-related muscle decline.
Beyond hormone deficiency: a framework for endocrine-immune-niche integration in aging skeletal muscle regeneration.
Lipin1 restores nNOS sarcolemmal localization and improves fatigue resistance in Duchenne muscular dystrophy.
Molecular genetics of skeletal muscle diseases associated with abnormal excitation-contraction coupling.
Exercise Regulates Mitochondrial Quality Control: Maintenance and Remodeling of Skeletal Muscle Homeostasis.
Interleukin-1 signaling contributes to endurance training-induced skeletal muscle adaptations.
Aging preserves mTORC1 but attenuates JNK-SMAD2L signaling sensitivity to passive stretch-induced tension development in isolated mouse skeletal muscle.
Meloxicam protects against muscle and metabolic decline in ageing through Cdon restoration and oxidative stress modulation.
Physiological functions of MCT1 and MCT4 in intramuscular lactate shuttle, exercise performance and glucose disposal.
ATP6AP2 dysregulation as a central hub in DMD pathogenesis: An integrated multi-omics and therapeutic study.
Extracellular vesicles derived from immobilization-induced atrophic muscle of male mice contain distinct microRNA profiles and impact mRNA profiles in brain neurons.
Circulating granulocyte colony-stimulating factor as a sex-unbiased global marker of lung and colorectal cancer cachexia pre-clinical models.
DNA methylation signatures in skeletal muscle associated with physical function in healthy older adults.
Long non-coding RNAs in exercise: the hidden regulators of adaptation.
Exercise slows ovarian aging.
Heat Shock Proteins and Exercise in Skeletal Muscle Insulin Resistance: Protective Mechanisms and Therapeutic Potential.
Glucagon receptor deficiency is associated with glucocorticoid receptor activation and proteolytic remodeling in gastrocnemius of male mice.
Mitochondrial Inflammation and Muscle Aging: Targeting the Inflammatory Microenvironment in Sarcopenic Muscle.
Vesicular Communication in the Bone-Muscle Unit: Physiological Functions, Aging, and Therapeutic Potential.
NAMPT shows tissue-dependent immune-metabolic associations in osteoarthritic synovium and aging-related skeletal muscle.
Vitamin D as a Modulator of Sarcopenia in Women: Interactions with Dietary Patterns and Physical Exercise.
Ovarian hormone loss modifies the nucleic acid cargo of circulating extracellular vesicles and skeletal muscle metabolism after acute exercise in rats.
Alterations of actin in aging.
A semi-automated pipeline for morphological analysis of myonuclei along single muscle fibers.
Interplay of βPS and βν integrins in Drosophila muscle functioning.
An Ultrastructural and Proteomic Analysis in DM1 Young Adults' Myoblasts: Stressed RER and Mitochondrial Dysfunction Involvement.
Exercise intensity modulates interorgan communication and is associated with cardiometabolic health outcomes in humans.

Cell Rep. 2026 Aug 12. pii: S2211-1247(26)00901-0. [Epub ahead of print]45(8): 117823

Temporal multi-omic analysis uncovers sex-biased molecular programs underlying skeletal muscle adaptation to endurance training.

MoTrPAC study group

  Exercise training confers broad health benefits, yet molecular regulators of skeletal muscle adaptation, particularly sex-specific mechanisms, remain incompletely understood. Integrating new and previously published multi-omics data from the molecular transducers of physical activity consortium (MoTrPAC), we characterized metabolomic, epigenomic, transcriptomic, proteomic, and post-translational modification (PTM) responses to 1-8 weeks of endurance exercise training in male and female rat gastrocnemius. While transcriptomic and proteomic responses were largely sex-concordant, there were distinct sex-specific training-induced PTM signatures, particularly in the redox proteome. Females exhibited decreased mitochondrial protein cysteine oxidation alongside increased oxidation of glycolytic proteins relative to males, suggesting sex-biased subcellular reactive oxygen species (ROS) dynamics. Multi-omic factor analysis (MOFA) identified coordinated sex-concordant molecular programs and further supported female-specific mechanisms of redox buffering with training. Together, these findings indicate that sex-specific skeletal muscle exercise adaptations are particularly evident at the PTM level in rats, and identify future avenues for precision exercise health and medicine.

Keywords:  CP: Metabolism; PTMs; cysteine oxidation; endurance exercise; exercise training; mitochondrial remodeling; multi-omics; post-translational modifications; sex differences; skeletal muscle, proteomics

DOI:  https://doi.org/10.1016/j.celrep.2026.117823
iScience. 2026 Aug 21. 29(8): 117000

Comprehensive transcriptomic profiling reveals impaired polyamine metabolism as a contributor to age-related muscle decline.

Veronica Ruggieri, Andrea Bracaglia, Lorenza Esposito, Nicola Tumino, Piera Filomena Fiore, Sofia Botta, Alberto Macone, Jessica Ohana, Marina Bouchè, Lucia Latella, Lorenzo Giordani, Luca Madaro.

  Sarcopenia, the age-related decline in skeletal muscle mass and function, profoundly affects skeletal muscle structure and performance. We present a spatial transcriptomic atlas of skeletal muscle from young and aged mice, resolving transcriptional reprogramming across fiber types and tissue compartments. Our analyses reveal alterations in sarcomeric organization, excitation-contraction coupling, oxidative stress responses, and fiber type-specific metabolic rewiring. Conserved molecular signatures across muscles and species highlight Car3 as a potential biomarker of sarcopenia. We also uncover a selective downregulation of polyamine biosynthetic enzymes, leading to reduced spermidine levels in aged muscle. This decline affects muscle-resident populations, as limiting polyamine metabolic flux in both murine and human fibro-adipogenic progenitors (hFAPs) induces aging-like features, including myofibroblast differentiation, extracellular matrix dysregulation, and impaired ability to support myogenesis. Together, our findings reveal spatially organized, fiber type-specific, and polyamine-linked mechanisms of muscle aging and position the polyamine pathway as a promising therapeutic target.

Keywords:  Amd1; fibro-adipogenic progenitors; polyamines; sarcopenia; spatial transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2026.117000
Front Immunol. 2026 ;17 1906969

Beyond hormone deficiency: a framework for endocrine-immune-niche integration in aging skeletal muscle regeneration.

Laura Perin, Stefano Da Sacco, Yan-Yun Liu, Gregory A Brent, Anna Milanesi.

  Thyroid hormone (TH) signaling is widely recognized as an important regulator of skeletal muscle regeneration, yet the mechanisms by which aging alters TH-dependent regenerative responses remain unresolved. Current models generally assume that age-associated regenerative decline reflects reduced thyroid hormone receptor (THR) signaling resulting from alterations in hormone availability, receptor expression, or downstream transcriptional activity. However, several observations challenge this view, including the persistence of THR activity in aged tissues, the limited efficacy of thyroid hormone replacement in restoring regeneration, and the distinct regenerative phenotypes observed in aging and hypothyroidism. Here, we propose the hypothesis that aging does not primarily impair skeletal muscle regeneration through loss of THR signaling, but through disruption of endocrine-immune-niche integration. In this framework, THR signaling functions as a systems-level coordinator that integrates endocrine signals with stromal remodeling, immune responses, and intercellular communication networks required for effective tissue repair. To evaluate whether available evidence is consistent with this hypothesis, we integrate published studies with analyses of publicly available murine single-cell transcriptomic, chromatin-accessibility, and ligand-receptor datasets spanning skeletal muscle regeneration, aging, and hypothyroidism. These associative analyses suggest that substantial components of THR activity remain detectable during aging, whereas coordination between THR signaling, macrophage remodeling, extracellular-matrix programs, inflammatory pathways, and Notch-mediated communication is altered. The findings are associative and do not establish causality; rather, they provide a hypothesis-generating framework for experimental testing. We propose that aging represents a state of impaired endocrine-immune-niche integration in which thyroid hormone signaling remains partially active but becomes increasingly uncoupled from the regenerative programs it normally coordinates. This framework offers a possible unifying explanation for several previously disconnected observations and generates experimentally testable predictions regarding endocrine-immune communication during tissue repair and aging.

Keywords:  aging; endocrine immune network factors; muscle stem cells; skeletal muscle regeneration; thyroid hormone signaling

DOI:  https://doi.org/10.3389/fimmu.2026.1906969
Am J Physiol Cell Physiol. 2026 Aug 13.

Lipin1 restores nNOS sarcolemmal localization and improves fatigue resistance in Duchenne muscular dystrophy.

Ayat Azzam, Abdulrahman Jama, John Karanja Kamau, Lixin Dong, Brooklyn Morris, Pooneh Hajmirza Mohammadi Kamalabadi, Denish Maharjan, Abdullah A Alshudukhi, Hongmei Ren.

  In Duchenne muscular dystrophy (DMD), nNOS is mislocalized from the sarcolemmal membrane and exhibits reduced expression and activity, impairing vasomodulation and contributing to increased muscle fatigue. Identification of upstream regulators that restore nNOS localization and function may provide therapeutic strategies to improve muscle performance in dystrophic muscle. In this study, we investigated the role of lipin1 in regulating nNOS expression, sarcolemmal localization, and NOS activity in skeletal muscle. Lipin1 deficiency significantly reduced nNOS expression and total NOS enzymatic activity, whereas lipin1 overexpression enhanced these parameters. Skeletal muscle-specific lipin1 knockout mice (lipin1Myf5cKO) exhibited increased muscle fatigue, consistent with impaired nNOS-dependent muscle function. In contrast, transgenic lipin1 restoration in dystrophic muscle (mdx:lipin1Tg/0) restored nNOS expression and sarcolemmal localization and improved fatigue resistance. Our findings suggest that lipin1 promotes nNOS sarcolemmal localization, potentially through stabilization of membrane-associated protein complexes, and enhances nNOS expression through a lipin1/DAG/PKD/CREB signaling axis. Collectively, these findings identify lipin1 as an important regulator of nNOS expression and localization in skeletal muscle and support lipin1 restoration as a potential therapeutic strategy for DMD.

Keywords:  Duchenne Muscular Dystrophy; Dystrophin; lipin1; muscle fatigue; nNOS

DOI:  https://doi.org/10.1152/ajpcell.00547.2025
J Hum Genet. 2026 Aug 10.

Molecular genetics of skeletal muscle diseases associated with abnormal excitation-contraction coupling.

Yukari Endo.

Skeletal muscle excitation-contraction coupling (ECC) is a highly specialized process that converts membrane depolarization into contraction through tightly regulated intracellular Ca²⁺ dynamics. Recent advances in molecular genetics have expanded the spectrum of skeletal muscle disorders associated with ECC-related proteins, including congenital myopathies, malignant hyperthermia susceptibility, exertional rhabdomyolysis, exertional heat illness, and related episodic disorders. Although these disorders have traditionally been classified according to clinical manifestations, pathological findings, and causative genes, accumulating evidence suggests that genetically and clinically heterogeneous disorders converge on overlapping abnormalities in intracellular Ca²⁺ handling and ECC function. This review provides an integrative overview of ECC-related skeletal muscle disorders from the perspective of shared abnormalities in intracellular Ca²⁺ handling and the molecular mechanisms that underlie them. We discuss how pathogenic variants affecting the voltage-sensing skeletal muscle L-type calcium channel (CaV1.1), the ryanodine receptor type 1 (RyR1), and other triad-associated proteins disrupt Ca²⁺ release from the sarcoplasmic reticulum (SR), luminal Ca²⁺ regulation, and SR Ca²⁺ reuptake, leading to diverse but partially convergent phenotypes. We also discuss secondary pathological changes associated with chronic intracellular Ca²⁺ dysregulation, including mitochondrial dysfunction, oxidative stress, and skeletal muscle remodeling. Finally, we present a functional perspective centered on intracellular Ca²⁺ handling that complements conventional genetic and clinicopathological classifications of ECC-related skeletal muscle disorders.

DOI: https://doi.org/10.1038/s10038-026-01499-2
Biology (Basel). 2026 Jul 27. pii: 1240. [Epub ahead of print]15(15):

Exercise Regulates Mitochondrial Quality Control: Maintenance and Remodeling of Skeletal Muscle Homeostasis.

Huiying Zhao, Min Chen.

  Skeletal muscle, as the largest metabolic organ, maintains its homeostasis highly dependent on the precise regulation of mitochondrial quality control. Mitochondrial quality control (MQC) encompasses three core aspects: mitochondrial biogenesis, dynamic balance, and autophagy. All of these jointly ensure mitochondrial network functional integrity. MQC imbalance is mainly manifested as decreased mitochondrial biosynthesis capacity, disordered fusion and division dynamics, and reduced autophagy clearance efficiency. MQC imbalance can lead to atrophy of skeletal muscles, metabolic dysfunction, and decline in motor function. As a physiological stress stimulus, exercise can precisely regulate MQC through multiple targets and pathways and restore the homeostasis of skeletal muscles. Exercise activates AMPK-PGC-1α to promote mitochondrial biogenesis, regulates MFN1/2, OPA1, and DRP1 to optimize mitochondrial dynamics, and activates the PINK1/Parkin pathway and receptor-mediated autophagy pathway to enhance mitochondrial autophagy. The regulatory effects of different exercise modes on MQC vary significantly. Aerobic exercise focuses on promoting mitochondrial biogenesis and fusion, while high-intensity interval training can more efficiently activate the autophagy pathway. Resistance exercise, on the other hand, requires a longer period to manifest its regulation of dynamic proteins. This article systematically reviews the molecular regulatory mechanism of MQC and its impact on skeletal muscle imbalance and elaborates on the mechanisms by which exercise regulates the remodeling of skeletal muscle through MQC. This article also further compares the differential effects of different exercise modes on the regulation of mitochondrial quality control to maintain skeletal muscle homeostasis. Future research needs to further explore the dose and effect relationship of exercise on regulating MQC and the optimal combination of exercise modes to provide a scientific basis for formulating precise and safe exercise intervention strategies.

Keywords:  exercise; mitochondria; mitochondrial quality control; skeletal muscle

DOI:  https://doi.org/10.3390/biology15151240
Am J Physiol Regul Integr Comp Physiol. 2026 Aug 09.

Interleukin-1 signaling contributes to endurance training-induced skeletal muscle adaptations.

Azuma Naito, Tatsuya Sato, Nao Tokuda, Nao Yamauchi, Ayaka Niibori, Kazuma Okada, Takashi Yamada.

  Interleukin (IL)-1 is widely recognized as an inflammatory cytokine induced in response to muscle injury, where it contributes to the clearance of damaged fibers and supports subsequent regenerative and reparative processes. In contrast, IL-1 derived from infiltrating neutrophils in response to transient, non-damaging exercise has been reported to regulate energy metabolism during endurance exercise. Therefore, in the present study, we investigated the role of IL-1 in skeletal muscle endurance adaptations induced by chronic endurance training (ET). Thirteen-week-old BALB/c wild-type (WT) mice and mice deficient in both IL-1α and IL-1β (IL-1 knockout; IL-1 KO) were used. The left hindlimb was subjected to ET induced by electrical stimulation of the triceps surae muscle three times per week for five weeks, while the right hindlimb served as a control. Baseline muscle endurance did not differ between WT and IL-1 KO mice. Following ET, muscle endurance and mitochondria respiration were significantly increased in WT mice but not in IL-1 KO mice. Moreover, ET induced increases in citrate synthase activity and the expression of PGC-1α, mitochondrial respiratory chain complexes I and III, and hexokinase 2 exclusively in WT mice. A single bout of exercise significantly increased IL-1β mRNA, but not IL-1α mRNA, in WT mice. In addition, exercise-induced phosphorylation of p38 MAPK and increases in PGC-1α-b and hexokinase 2 mRNA expression were attenuated in IL-1 KO mice. These findings suggest that IL-1 signaling is associated with ET-induced improvements in muscle endurance and mitochondrial quantity and quality, possibly through activation of the p38 MAPK pathway.

Keywords:  endurance training; interleukin-1; mitochondrial adaptations; p38 MAPK; skeletal muscle

DOI:  https://doi.org/10.1152/ajpregu.00125.2026
Exp Gerontol. 2026 Aug 04. pii: S0531-5565(26)00244-5. [Epub ahead of print]223 113265

Aging preserves mTORC1 but attenuates JNK-SMAD2L signaling sensitivity to passive stretch-induced tension development in isolated mouse skeletal muscle.

Jonas Boritz Kristiansen, Jacob Andresen, Jesper Emil Jakobsgaard, Kristian Vissing.

   INTRODUCTION: Aging is associated with impaired skeletal muscle mass and function, often attributed to reduced sensitivity to anabolic stimuli. This study investigated whether aging influences the sensitivity of key anabolic signaling pathways to mechanical tension development in skeletal muscle.
METHODS: Using an ex vivo model, extensor digitorum longus (EDL) muscles from adult (16 weeks) and old (24 months) female mice were subjected to a standardized passive stretch protocol, with contralateral muscles serving as controls. During recovery, phosphorylation of proteins related to downstream mTORC1 and JNK-SMAD2-L signaling were assessed by immunoblotting.
RESULTS: Passive stretch significantly increased phosphorylation of mTORC1-related proteins (mTOR, p70S6K, rpS6, and 4E-BP1) in both adult and old muscles, with no significant differences between age groups, indicating preserved mTORC1 signaling sensitivity to mechanical tension with aging. In contrast, the magnitude of activation of JNK and SMAD2-L signaling was attenuated in old muscles.
DISCUSSION: Our findings reveal that mechanosensitive anabolic signaling is differentially affected by aging. While the intrinsic capacity for mTORC1 activation in response to mechanical tension appears to be preserved with aging, JNK-SMAD2L signaling exhibits reduced mechanosensitivity in aged muscle. This divergence suggests that aging selectively impairs tension-sensitive transcriptional pathways, potentially constraining muscle remodeling despite preserved translational signaling capacity. These findings further imply that age-related deficits observed in vivo may, at least in part, arise from systemic influences rather than intrinsic defects adhering to mTORC1 mechanotransduction.

Keywords:  Aging; Anabolic signaling; Ex vivo; JNK; Mechanotransduction; Passive stretch; SMAD; Skeletal muscle; mTORC1

DOI:  https://doi.org/10.1016/j.exger.2026.113265
Exp Mol Med. 2026 Aug 12.

Meloxicam protects against muscle and metabolic decline in ageing through Cdon restoration and oxidative stress modulation.

Ju-Hyeon Bae, Hyun-Kyung So, Yideul Jeong, Jeongmin Park, June Kim, Tae Young Kim, Young-Eun Leem, Tuan Anh Vuong, Jiwoong Jang, Moongi Ji, Hyon-Seung Yi, Il-Young Kim, Man-Jeong Paik, Sang-Jin Lee, Gyu-Un Bae, Jong-Sun Kang.

Sarcopenia is characterized by progressive decline in skeletal muscle mass and function, driven in part by impaired mitochondrial homeostasis and redox imbalance. However, the upstream regulators that integrate metabolic resilience with muscle integrity during ageing remain poorly defined. Here, we identify the cell adhesion molecule Cdon as a conserved determinant of adult muscle maintenance whose expression declines with human aging, sarcopenia and muscle-wasting disease. Reduced Cdon expression was associated with transcriptional atrophy signatures, metabolic insufficiency and reduced myofibre size. Using a Cdon promoter-based screen, we identified meloxicam (Mcam) as a small molecule inducer of Cdon that enhances myogenic differentiation, increases muscle mass and function in young mice and mitigates age-related muscle atrophy. Mcam treatment also improved neuromuscular conduction and systemic metabolic parameters, including blood glucose regulation and hepatic lipid accumulation. In aged muscle, Mcam normalized cysteine accumulation, restored redox balance, improved mitochondrial metabolism and reduced oxidative stress. Mechanistically, Mcam activated Ampk signalling to preserve Cdon expression under oxidative challenge and support antioxidant and mitochondrial quality control pathways. Together, these findings identify Cdon decline as a hallmark of muscle ageing and demonstrate that Mcam preserves muscle integrity by reestablishing redox and metabolic homeostasis through Ampk-dependent maintenance of Cdon. Age-related decline of Cdon is a key molecular feature of skeletal muscle dysfunction. In this study, meloxicam restored Cdon expression through Ampk activation, thereby preserving muscle integrity and functional capacity in aged muscle. Mechanistically, meloxicam normalized cysteine metabolism and elevates Gpx4 expression, improving glutathione buffering and suppressing excessive reactive oxygen species accumulation. Activation of the Ampk-Cdon axis was associated with maintenance of mitochondrial homeostasis and redox balance. Together, these findings identify Cdon as a potential therapeutic target for age-associated skeletal muscle degeneration.

DOI: https://doi.org/10.1038/s12276-026-01804-1
Am J Physiol Cell Physiol. 2026 Aug 13.

Physiological functions of MCT1 and MCT4 in intramuscular lactate shuttle, exercise performance and glucose disposal.

Zinan Wang, Shixuan Zhuo, Chenchen Li, Jing Zhu, Shuying Wang, Yan Chen.

  Lactate shuttling between glycolytic and oxidative muscle fibers via monocarboxylate transporters MCT1 and MCT4 is fundamental to muscle energy homeostasis, yet the physiological necessity of these two transporters remained obscured by functional redundancy. To investigate the significance of these two transporters in intermuscular lactate shuttle, we generated and characterized skeletal muscle-specific MCT1/4 double-knockout (MCT1/4-mKO) mice alongside with MCT4 single-knockout mice (MCT4-mKO). While MCT4-mKO mice had minimal metabolic disturbances, MCT1/4-mKO mice exhibited markedly reduced lean mass, impaired exercise endurance together with enhancement of insulin-stimulated glucose disposal under normal chow diet condition. The blood lactate level after exercise and the maximum grip strength was mitigated in both MCT4-mKO and MCT1/4-mKO mice. Plasma membrane localization of GLUT4 was robustly increased in the skeletal muscle in MCT1/4-mKO mice upon insulin treatment. These findings highlight that the intramuscular lactate shuttle mediated by MCT1 and MCT4 is critical for maintaining skeletal muscle mass, contractile performance and insulin sensitivity.

Keywords:  MCT1; MCT4; exercise performance; insulin sensitivity; lactate shuttle

DOI:  https://doi.org/10.1152/ajpcell.00414.2026
Int Immunopharmacol. 2026 Aug 13. pii: S1567-5769(26)01093-3. [Epub ahead of print]188 117247

ATP6AP2 dysregulation as a central hub in DMD pathogenesis: An integrated multi-omics and therapeutic study.

Lin Zhou, Yu Zhang, Xinxin Tan, Lihong Tao, Xuan Wu.

  Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting and persistent chronic inflammation, yet the multi-lineage cellular drivers of its pathogenesis remain incomplete. In this study, single-cell RNA sequencing (scRNA-seq) identified Atp6ap2 as a profoundly upregulated gene across multiple skeletal muscle cell types-particularly endothelial cells, fibroblasts, and myoblasts-in both mdx and severe mdx mice. Weighted gene co-expression network analysis (WGCNA) linked Atp6ap2 expression to DMD progression, while enrichment analyses revealed that its dysregulation severely impairs vascular homeostasis and extracellular matrix integrity via the PI3K-Akt, focal adhesion, and cell cycle pathways. Utilizing Connectivity Map (CMap) analysis, we identified temozolomide (TMZ) as a top pharmacological candidate capable of reversing the ATP6AP2-associated gene signature. In vivo validation demonstrated that TMZ administration significantly enhanced motor coordination, balance, and grip strength in mdx mice, while markedly preserving dystrophic muscle architecture, reducing myofiber necrosis, and alleviating interstitial fibrosis. Mechanistically, integrated transcriptomic and metabolomic profiling revealed that TMZ induced profound metabolic and signaling shifts, modulating the Notch, MAPK, and Ras pathways, as well as autophagy and glycerophospholipid metabolism. Furthermore, scRNA-seq and cell-cell communication analyses indicated that TMZ dynamically reorganized multicellular networks, decreasing aberrant fibroblast and endothelial interactions. Crucially, immunofluorescence and Western blot validations confirmed that TMZ drastically attenuated the infiltration of F4/80-positive macrophages and suppressed their pro-inflammatory M1 polarization (indicated by reduced co-localization with iNOS and ATP6AP2), while successfully reversing the dysregulation of the ATP6AP2 axis and restoring its downstream targets MAP4K2, DGKE, and EFNA1. Collectively, our findings demonstrate that TMZ mitigates dystrophic pathology by targeting the ATP6AP2 signaling axis and dampening macrophage-mediated inflammatory responses, highlighting its potential as a novel immunopharmacological therapeutic strategy for DMD.

Keywords:  ATP6AP2; Duchenne muscular dystrophy; Metabolomics; Multi-omics integration; Single-cell RNA sequencing

DOI:  https://doi.org/10.1016/j.intimp.2026.117247
Physiol Rep. 2026 Aug;14(16): e71052

Extracellular vesicles derived from immobilization-induced atrophic muscle of male mice contain distinct microRNA profiles and impact mRNA profiles in brain neurons.

Noriaki Kawanishi, Shuichi Machida, Katsuhiko Suzuki.

  Muscle atrophy caused by inactivity leads to declines in multiple physiological functions, including brain function. Although skeletal muscle is known to secrete extracellular vesicles (EVs) such as exosomes, how inactivity-induced muscle atrophy alters the properties and functions of these EVs remains unclear. In this study, we investigated the effects of cast immobilization-induced muscle atrophy on the microRNA (miRNA) profiles of skeletal muscle-derived EVs in mice, as well as their impact on transcriptome changes in brain neurons. Muscle atrophy induced by cast immobilization significantly altered the microRNA profiles of skeletal muscle-derived EVs, with 25 microRNAs upregulated and 2 microRNAs downregulated compared with controls. Moreover, treatment of brain neurons with EVs derived from atrophic skeletal muscle markedly changed neuronal mRNA expression profiles. Gene Ontology (GO) analysis revealed that upregulated mRNAs in EV-treated neurons were enriched in genes involved in the positive regulation of programmed cell death, including apoptosis. Consistently, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis demonstrated activation of apoptosis-related signaling pathways in brain neurons. These findings suggest that muscle atrophy-induced alterations in skeletal muscle-derived EVs may contribute to brain dysfunction by promoting apoptotic processes in brain neurons.

Keywords:  brain neurons; exosomes; extracellular vesicles; microRNA; muscle atrophy

DOI:  https://doi.org/10.14814/phy2.71052
Exp Physiol. 2026 Aug 13.

Circulating granulocyte colony-stimulating factor as a sex-unbiased global marker of lung and colorectal cancer cachexia pre-clinical models.

Francielly Morena, Eleanor R Schrems, Ana Regina Cabrera, Ruqaiza Muhyudin, Sepideh Shakeri, Stavroula Tsitkanou, Mark Viggars, Tyrone A Washington, Nicholas P Greene.

  Cancer cachexia, affecting up to 80% of patients with advanced cancer, is characterized by metabolic and inflammatory dysregulation driven by tumour- and host-derived factors. Although cytokines are central to cachexia pathogenesis, their circulating profiles and transcriptional relevance across models and sexes remain incompletely defined. We characterized plasma cytokines and skeletal muscle inflammatory signatures in multiple cachexia models, including Lewis Lung Carcinoma (LLC), Colon-26 (C26) and ApcMin/+ mice. Animals were monitored for 4 weeks (LLC), 25 days (C26) or until ∼20 weeks of age (ApcMin/+) per model appropriate endpoints. Publicly available RNA-sequencing datasets from gastrocnemius (LLC) and tibialis anterior (C26 and ApcMin/+) muscles were integrated with plasma profiling using a Mouse Cytokine/Chemokine 32-Plex assay. To enhance accessibility and reproducibility, we developed an interactive Shiny application - thecachexiatlas/Cytokine Explorer - enabling dynamic visualization of cytokine levels, transcriptional signatures and phenotype correlations across models and sexes. Cytokine receptor encoding genes (Il6ra, Il4ra, Csf3, Osmr) and inflammatory pathways were consistently enriched in skeletal muscle of cachectic animals across models and sexes. Among circulating cytokines, granulocyte colony-stimulating factor (G-CSF) was uniquely elevated in all models and both sexes. Elevated G-CSF levels exhibited stronger negative correlations with tibialis anterior muscle mass than the commonly used cytokine interleukin (IL)-6, particularly when expressed as the ratio of G-CSF to the anti-inflammatory cytokine IL-13. The G-CSF:IL-13 ratio may represent a robust global biomarker of cachexia severity. The Cytokine Explorer Shiny app provides an open, interactive platform to facilitate hypothesis generation and advance research in cancer cachexia.

Keywords:  RNA sequencing; atrophy; cancer cachexia; chemokine; cytokine; inflammation; skeletal muscle

DOI:  https://doi.org/10.1113/EP093809
Geroscience. 2026 Aug 08.

DNA methylation signatures in skeletal muscle associated with physical function in healthy older adults.

Xiaoxiao Wen, Mingjing Chen, Guanhong Miao, Christopher Wu, Anna Picca, Javier A Tamargo, Xiangyang Lou, Kevin Wu, Stephen Anton, Christiaan Leeuwenburgh, Jinying Zhao.

  Despite the substantial variability in physical function among older adults, the molecular mechanisms remain poorly characterized, particularly within skeletal muscle. This study aimed to determine the patterns of DNA methylation in skeletal muscle associated with physical function in healthy older adults. We analyzed DNA methylation (EPIC v2 array; 875,554 CpG sites) in skeletal muscle from 92 healthy older adults (median age 74; 62% female). Associations were examined across five phenotypes: Short Physical Performance Battery (SPPB), 6-min walk test (6MWT), handgrip strength, perceived disability (PAT-D), and lifestyle health (modified Life's Essential 8). Linear regression models adjusted for age, sex, race, BMI, and muscle fiber composition. Genomic inflation corrected via the BACON method (FDR < 0.05). Gene set enrichment analysis was performed on suggestive hits (FDR < 0.1). We identified significant differentially methylated probes (DMPs) and regions (DMRs) across all phenotypes: SPPB (70 DMPs, 22 DMRs), 6MWT (16 DMPs, 566 DMRs), handgrip strength (2 DMRs), PAT-D (19 DMPs, 1 DMR), and lifestyle health (2 DMPs). DMRs largely overlapped promoters. Identified genes overlapped known musculoskeletal and neurological GWAS hits, including RUNX2 and FOXL1 (bone mineral density), IGFBP3 (muscle mass), and NEK1 and SHANK1 (neurological function). Enrichment analysis revealed that 6MWT-associated genes relate to nervous and skeletal system development, while handgrip-associated genes involve cytoskeletal dynamics and protein assembly. Epigenetic variation in aging skeletal muscle is associated with physical function. The enrichment of pathways related to nervous and musculoskeletal development suggests specific epigenetic mechanisms underlying functional decline, offering potential targets for intervention in older adults.

Keywords:  DNA methylation; Epigenetics; Healthy aging; Physical function; Skeletal muscle

DOI:  https://doi.org/10.1007/s11357-026-02410-9
Pflugers Arch. 2026 Aug 15. pii: 73. [Epub ahead of print]478(9):

Long non-coding RNAs in exercise: the hidden regulators of adaptation.

Qin Zhang, Zhouren Zhang, Cai Ren, Ping Xiang, Xinhua Li, Ru Ren, Lianting Feng, Jicheng Chen.

  Regular physical activity elicits coordinated molecular adaptations across skeletal muscle, the cardiovascular system, metabolic organs and the brain, underpinning improvements in performance and cardiometabolic health. While classical signaling pathways such as AMPK-PGC‑1α, Ca²⁺/calcineurin, and mTORC1 have been extensively characterized, long non-coding RNAs (lncRNAs) have recently emerged as key regulators of exercise-induced remodeling. Here, we synthesize current evidence on lncRNAs as molecular mediators of exercise adaptations, drawing on mechanistic studies and systems-level transcriptomics. In skeletal muscle, the exercise-induced lncRNAs CYTOR and TUG1 modulate fast-twitch myogenesis, mitochondrial function and fiber-type specification. In the heart, CPhar, lncExACT1 and Mhrt779 discriminate physiological from pathological hypertrophy and encode antihypertrophic "memory," whereas endothelial NEAT1 integrates aerobic training with m⁶A-modulated pyroptosis and atheroprotection. MALAT1 mediates neuroprotection after exercise preconditioning in ischemia/reperfusion models. Omics and network analyses reveal highly modality-, tissue- and cell-type-specific lncRNA programs during human training and across multiple organs. Emerging clinical data support circulating lncRNAs such as MALAT1 and HOTTIP as candidate biomarkers of vascular function and training adaptation. Collectively, lncRNAs constitute a hidden regulatory layer that shapes the quality, magnitude and persistence of exercise-induced adaptations. However, mechanistic evidence is currently limited to a small number of "flagships" lncRNAs, and non-muscle tissues and inter-organ communication remain underexplored. Priorities include functional validation of atlas-derived candidates, dissection of exerkine lncRNAs, and integration of lncRNA biology into precision exercise medicine.

Keywords:  Cardiac hypertrophy; Epigenetic adaptation; Exrcisee; Long non-coding RNA; Skeletal muscle

DOI:  https://doi.org/10.1007/s00424-026-03204-w
Nat Aging. 2026 Aug 14.

Exercise slows ovarian aging.

DOI: https://doi.org/10.1038/s43587-026-01176-1
Int J Mol Sci. 2026 Jul 24. pii: 6587. [Epub ahead of print]27(15):

Heat Shock Proteins and Exercise in Skeletal Muscle Insulin Resistance: Protective Mechanisms and Therapeutic Potential.

Mariam A Othman, Joo Hyun Kim, Khaled Y Kamal, John M Lawler.

  Heat shock proteins (HSPs) are a family of conserved molecular chaperons present in both prokaryotic and eukaryotic species, playing a crucial role in maintaining cellular proteostasis and enhancing stress resilience. HSPs have a multitude of roles in regulating cell signaling transduction, antioxidant defenses, apoptosis, and protein folding, thereby contributing to overall cellular homeostasis. Insulin resistance is characterized by elevated oxidative stress, dysregulated pro-inflammatory signaling, and impaired cellular stress response, ultimately leading to deficient glucose uptake in skeletal muscle. Many studies have illustrated the benefits of exercise in improving insulin resistance and reducing the risk of metabolic disorders, such as type 2 diabetes. Habitual exercise and lifestyle modifications have been shown to activate heat shock response, enhancing HSP70 expression and promoting cellular adaptations that protect against metabolic dysfunction. However, the link between HSPs, particularly HSP70, and skeletal muscle insulin resistance remains complex and not fully elucidated. In this review, we discuss the mechanistic pathways by which HSP70 modulates insulin resistance, mitochondrial function, and inflammatory responses in skeletal muscle. Additionally, we discuss the protective effects of exercise-induced HSP70 expression and its potential as a therapeutic target for improving insulin sensitivity and metabolic health.

Keywords:  exercise; heat shock proteins; insulin resistance; molecular pathways; skeletal muscles

DOI:  https://doi.org/10.3390/ijms27156587
Am J Physiol Endocrinol Metab. 2026 Aug 09.

Glucagon receptor deficiency is associated with glucocorticoid receptor activation and proteolytic remodeling in gastrocnemius of male mice.

Xuanxuan Bai, Tongyu Zhang, Chao Zhang, Mingyu Li.

  Glucagon receptor (GCGR) signaling plays a central role in systemic metabolic regulation. However, its role in skeletal muscle protein homeostasis remains poorly understood. In this study, we demonstrated that skeletal muscle from male GCGR-deficient mice exhibited preferential gastrocnemius atrophy accompanied by elevated intramuscular free amino acid levels and hyperaminoacidemia. Transcriptomic and biochemical analyses revealed activation of glucocorticoid receptor (GR) signaling together with induction of proteolytic pathways, as reflected by increased TRIM63 and FBXO32 levels, elevated LC3B-II/I ratio, and reduced p62 levels. Notably, GCGR deficiency was associated with increased corticosterone and subsequent GR activation. In cultured myotubes, serum from male Gcgr-/- mice induced GR activation, enhanced proteolysis, and increased intracellular free amino acid levels, all of which were attenuated by GR antagonism. Consistently, dexamethasone stimulation increased net amino acid accumulation in the culture medium. Moreover, the GR activation-resulted gastrocnemius atrophy was alleviated by GLP-1R antagonism. These findings link GCGR deficiency to GR activation, gastrocnemius proteolysis, hyperaminoacidemia and elevated GLP-1 signaling, suggesting a role for skeletal muscle in systemic amino acid homeostasis under impaired GCGR signaling.

Keywords:  amino acid homeostasis; gastrocnemius atrophy; gastrocnemius proteolysis; glucagon receptor; glucocorticoid receptor activation

DOI:  https://doi.org/10.1152/ajpendo.00076.2026
Aging Dis. 2026 Aug 03.

Mitochondrial Inflammation and Muscle Aging: Targeting the Inflammatory Microenvironment in Sarcopenic Muscle.

Xuesong Wang, Shannah Erasmus, Zewen Chu, Xiaomin Tu, Tursen Alima, Yajie Tao, Lei Fang.

Sarcopenia is an age-related progressive degenerative disorder of skeletal muscle characterized by declining muscle mass, strength, and function. Increasing evidence indicates that chronic low-grade inflammation plays an important contributory role in its pathogenesis. The inflammatory microenvironment contributes to sarcopenia through complex interactions involving cellular senescence, mitochondrial dysfunction, and sustained inflammatory signaling, forming a self-reinforcing pathological cycle within skeletal muscle. This review synthesizes current evidence on the molecular mechanisms underlying inflammation-driven sarcopenia, with particular emphasis on how inflammatory signaling disrupts protein turnover and satellite cell metabolism. In addition, exercise is examined as a precision "hormone-like" intervention tailored to different sarcopenia phenotypes, highlighting the distinct mechanisms through which resistance training, aerobic exercise, and combined training modulate the senescence-associated phenotype and inflammatory responses. The review further evaluates anti-inflammatory therapeutic strategies, including nutritional interventions, pharmacotherapy, and acupuncture. These approaches improve muscle health by restoring immune balance, enhancing mitochondrial function, modulating the gut-muscle axis, reducing oxidative stress, and promoting the clearance of senescent cells. Finally, emerging precision medicine frameworks and multi-omics strategies that may support individualized sarcopenia management are discussed. Overall, this review provides an integrated perspective on inflammatory signaling in sarcopenia and outlines potential therapeutic strategies targeting the inflammatory microenvironment, offering insights for future research and clinical management.

DOI: https://doi.org/10.14336/AD.2026.0331
Cells. 2026 Aug 04. pii: 1413. [Epub ahead of print]15(15):

Vesicular Communication in the Bone-Muscle Unit: Physiological Functions, Aging, and Therapeutic Potential.

Virginia Veronica Visconti, Chiara Greggi, Antonio Matticari, Riccardo Iundusi, Elena Gasbarra, Annalisa Botta, Umberto Tarantino.

  Extracellular vesicles (EVs) have emerged as fundamental pillars of intercellular communication, acting as primary mediators of the bidirectional biochemical crosstalk within the integrated bone-muscle unit. This review provides a comprehensive synthesis of EV-mediated signaling across the bone-muscle axis, offering a side-by-side mapping of vesicular biogenesis, cargo composition, and functional roles in both tissues. Under physiological conditions, skeletal muscle- and bone-derived EVs orchestrate tissue homeostasis, adaptations to physical exercise, myogenesis, and bone remodeling by transferring unique molecular cargos of proteins and specific microRNAs. However, aging induces a profound remodeling of the EV secretome toward a senescent profile characterized by harmful vesicular factors. This dysfunctional vesicular signaling impairs both muscle regeneration and osteogenesis, directly contributing to the pathogenesis of interconnected age-related disorders like sarcopenia, osteoporosis, and osteosarcopenia. Concurrently, circulating EVs represent valuable, minimally invasive biomarkers for early diagnosis. On the therapeutic front, this review critically evaluates emerging EV-based approaches, utilizing mesenchymal stem cell-derived, bioengineered, or biomaterial-incorporated EVs, offering promising, low-immunogenic alternatives to cell transplantation to enhance musculoskeletal tissue repair and restore bone-muscle homeostasis. Despite persisting technical challenges regarding large-scale production and standardization, targeting or leveraging EV-mediated communication represents one of the most innovative and revolutionary strategies to counteract age-related musculoskeletal decline. By unifying physiological mechanisms, age-related molecular reprogramming, and therapeutic engineering across both muscle and bone into a single narrative, this review provides a comprehensive framework to guide future research and clinical translation in musculoskeletal health.

Keywords:  bone; bone–muscle crosstalk; extracellular vesicles (EVs); muscle; musculoskeletal diseases; osteoporosis; sarcopenia

DOI:  https://doi.org/10.3390/cells15151413
Front Med (Lausanne). 2026 ;13 1853301

NAMPT shows tissue-dependent immune-metabolic associations in osteoarthritic synovium and aging-related skeletal muscle.

Qianyu He, Weikai Qin, Ximing Yu, Lin Jing, Qi Yan.

   Introduction: Nicotinamide phosphoribosyltransferase (NAMPT) is a key immune-metabolic regulator linking nicotinamide adenine dinucleotide (NAD) salvage, inflammatory signaling, and tissue stress responses, but whether it occupies comparable transcriptomic contexts in osteoarthritic synovium and skeletal muscle remains unclear.
Methods: We performed a retrospective multi-cohort transcriptomic analysis using public GEO datasets with separate discovery and external supporting analysis stages. Discovery analyses included knee osteoarthritis synovium cohorts GSE55235 and GSE55457 and aging-related skeletal muscle proxy cohorts GSE38718 and GSE25941. Muscle-side findings were interpreted with explicit separation between aging-related skeletal muscle proxy cohorts and the clinically phenotyped sarcopenia external-support cohort. NAMPT abundance was evaluated by differential expression analysis and effect-size synthesis, immune and metabolic pathway activity was quantified by single-sample gene set enrichment analysis, and disease-adjusted partial correlations were used to define discovery-stage association structure. External supporting analyses were then performed in GSE12021, GSE254682, and the clinically phenotyped sarcopenia cohort GSE111016 to assess whether the direction of NAMPT abundance differences was reproduced in independent disease-relevant cohorts.
Results: Across the discovery stage, NAMPT showed a downward abundance signal in both tissue contexts, although meta-analytic pooling in knee osteoarthritis synovium was limited by between-study heterogeneity. External datasets provided partial support for lower NAMPT expression in disease-relevant synovium in GSE12021 and in clinically phenotyped sarcopenia muscle in GSE111016, whereas GSE254682 showed the same direction without statistical significance. Discovery-stage disease-adjusted coupling analyses indicated that osteoarthritic synovium retained stronger NAMPT associations with inflammatory and glycolytic programs, whereas aging-related skeletal muscle proxy cohorts showed weaker immune coupling and a pattern more consistent with metabolic deficit. Cohort-stratified stability analyses suggested that these associations were directionally consistent in osteoarthritic synovium but weaker and more heterogeneous in the muscle proxy cohorts. A reduced external association analysis showed partial module-level consistency with this contrast, including preserved inflammatory linkage in GSE254682 and a more oxidative-phosphorylation-oriented pattern in GSE111016. Exploratory cohort-level separation analyses and therapeutic inference were retained as secondary analyses and were not interpreted as evidence of clinical utility or efficacy.
Discussion: These findings suggest reduced NAMPT abundance with partial external support together with observational discovery-stage evidence of tissue-dependent immune-metabolic association patterns, and they favor context-specific interpretation and targeted experimental follow-up rather than uniform extrapolation across tissues.

Keywords:  NAD salvage; external support; immunometabolism; knee osteoarthritis; sarcopenia; skeletal muscle aging; synovitis

DOI:  https://doi.org/10.3389/fmed.2026.1853301
Nutrients. 2026 Aug 02. pii: 2494. [Epub ahead of print]18(15):

Vitamin D as a Modulator of Sarcopenia in Women: Interactions with Dietary Patterns and Physical Exercise.

Ilaria Versari, Alberto Bavelloni, Camilla Sbrighi, Mirko Traversari, Irene Faenza, Sara Salucci.

  Women are particularly vulnerable to sarcopenia- a progressive, age-related condition characterized by the loss of skeletal muscle mass, strength, and physical performance- due to sex-specific hormonal and physiological changes, most notably the decline in estrogen levels after menopause. This increased risk highlights the critical importance of developing tailored, sex-specific strategies for prevention, diagnosis, and management. Among nutritional factors, vitamin D is increasingly recognized as a key regulator of skeletal muscle physiology, exerting direct effects on muscle tissue via vitamin D receptors and modulating the gene expression involved in muscle cell proliferation, protein synthesis, and mitochondrial function. This review aims to evaluate the synergistic roles of vitamin D, nutrition, and exercise in improving skeletal muscle function in women, with a specific focus on the prevention and management of sarcopenia. Vitamin D can contribute to skeletal muscle integrity by influencing fiber composition, preserving type II fibers, and preventing mass loss. Additionally, it promotes satellite cell activation, thereby supporting muscle repair and regeneration. Consequently, vitamin D supplementation can improve muscle strength, balance, and physical performance, while reducing the risk of falls, frailty, osteoporosis and sarcopenia. Recent studies suggest that vitamin D acts synergistically with diets enriched with whey protein and leucine, as well as with structured exercise programs, predominantly resistance training, to further enhance muscle function and bone health. This review critically examines the current evidence regarding these combined interventions in preserving and optimizing skeletal muscle function in older women, while also addressing the major limitations and inconsistencies in available studies. Understanding the collective impact of these strategies is crucial for developing personalized and effective strategies aimed at maintaining musculoskeletal health, physical performance, and functional independence throughout the female aging process.

Keywords:  nutritional interventions; physical exercise; postmenopausal women; skeletal muscle tissue; vitamin D

DOI:  https://doi.org/10.3390/nu18152494
Exp Physiol. 2026 Aug 10.

Ovarian hormone loss modifies the nucleic acid cargo of circulating extracellular vesicles and skeletal muscle metabolism after acute exercise in rats.

Veera Puumalainen, Anni Maja, Tia-Marje Korhonen, Tuuli A Nissinen, Eero Hulkko, Janne A Ihalainen, Maarit Lehti, Sira Karvinen.

  Loss of ovarian hormones (i.e., menopause) leads to negative effects on metabolic health. While exercise offers significant benefits, it seems to be insufficient to completely reverse these changes. The mechanisms by which exercise conveys the effects throughout the body are still poorly understood. Extracellular vesicles (EVs) are released into circulation during exercise. EVs carry small non-coding RNAs (sRNAs), such as microRNAs (miRs), which are proposed as mediators of the effects of exercise. We have previously shown that the miR response to acute exercise of EVs and high-density lipoprotein (HDL) is diminished in postmenopausal women with low oestrogen levels, which we were able to replicate here also in a rat model. In this study, we examined the effect of loss of ovarian hormones and acute exercise in the sRNA cargo of EV and HDL particles in female rats. We show for the first time that loss of ovarian hormones affects specifically the nucleic acid cargo of circulating EVs. We further show that the oestrogen responsive miRs regulate anaerobic glycolytic pathway. Finally, we demonstrate that the loss of ovarian hormones leads to higher anaerobic energy production during an acute bout of exercise, implicating an inferior ability to sustain aerobic energy production during exercise.

Keywords:  Raman spectroscopy; extracellular vesicles; high‐density lipoprotein; menopause; oestrogen deficiency; ovariectomy; small non‐coding RNA

DOI:  https://doi.org/10.1113/EP094085
J Cell Sci. 2026 Aug 01. pii: jcs264775. [Epub ahead of print]139(15):

Alterations of actin in aging.

Maxim Averbukh, Tiffany Wang, Gilberto Garcia, Ryo Higuchi-Sanabria.

  The actin cytoskeleton is a highly dynamic and evolutionarily conserved multi-protein complex that regulates cellular architecture, mechanics and intracellular organization. Although actin dynamics and organization have been extensively studied in development and some disease contexts, the role of the actin cytoskeleton in aging has only recently begun to be considered. Accumulating evidence across model organisms indicates that aging is accompanied by progressive actin disorganization, which can manifest as filament disassembly, aggregation and mislocalization, impacting cellular homeostasis. In this Review, we synthesize the current understanding of how actin integrity is maintained through chaperone networks, actin-binding proteins, transcriptional programs and post-translational modifications, and how these regulatory layers change during the aging process. We then describe how these changes emerge as links between cytoskeletal decline and core aging hallmarks, including loss of proteostasis, mitochondrial dysfunction and cellular senescence. We further examine how this actin-related cellular dysregulation contributes to age-associated diseases, including neurodegeneration, cancer and muscle degeneration. Finally, we highlight recent studies suggesting that targeted modulation of actin regulatory pathways might preserve cellular resilience and healthspan, while emphasizing the challenges and opportunities in therapeutically targeting such a fundamental cellular system.

Keywords:  Actin; Aging; Cancer; Neurodegeneration

DOI:  https://doi.org/10.1242/jcs.264775
iScience. 2026 Aug 21. 29(8): 116961

A semi-automated pipeline for morphological analysis of myonuclei along single muscle fibers.

Esben T Schroeder, Helia G Megowan, Madeline Luu, Adam Shuaib, Adam C Fries, Jake Searcy, Hans C Dreyer.

  Manual quantitation of skeletal muscle myonuclear number, spatial orientation, and morphology is time-consuming and subject to error and bias. To overcome these limitations, we developed and validated a semi-automated, quantitative, and reproducible image-analysis pipeline. The workflow combines FIJI-based preprocessing with custom Python scripts to process immunohistological images of individual muscle fibers, enabling high resolution and scalable quantification of nuclei. The analyses incorporate morphometric parameters including nuclear position, shape, and three-dimensional orientation, as well as centroid-to-skeleton distance and nearest-neighbor relationships to capture spatial patterns of myonuclear organization along the fiber. Outputs include per-fiber and biopsy-level summaries integrated with IMARIS metrics. This semi-automated approach provides a robust and efficient platform for high-throughput analysis of myonuclear number and structural features across large single fiber datasets.

Keywords:  ImageJ; automation; muscle; pipeline

DOI:  https://doi.org/10.1016/j.isci.2026.116961
Gene. 2026 Aug 09. pii: S0378-1119(26)00360-4. [Epub ahead of print]1011 150350

Interplay of βPS and βν integrins in Drosophila muscle functioning.

Ushashi Ain, Y Rishabh, Hena Firdaus.

  Integrins are conserved cell-adhesion receptors implicated in development and disease, including joint disorders and osteoarthritis. Unlike humans, which encode 18 α- and 8 β-subunits, Drosophila melanogaster carries only 5 α- and 2 β-integrins, offering a simplified system to dissect their functions. While βPS is established as essential for embryonic muscle attachment, the roles of the less-characterised βν subunit, and the extent of overlap between the two, remain unresolved. Here, we combined βν null mutants with tissue-specific βPS knockdowns to systematically define their contributions to muscle function. We find that βν is required during early development, where its absence impairs larval body wall muscle performance, but becomes largely dispensable for adult survival, flight and other locomotory activities. By contrast, βPS is indispensable throughout Drosophila development, including the indirect flight muscle (IFM) integrity, where its depletion disrupts sarcomere organisation, precisely the H-zone width and downregulates thin filament genes. Notably, βν assumes supplementary roles in muscle development, with its transcript levels getting lowered when βPS is compromised. Again, in the functionally compromised larval muscles of βν nulls, βPS transcript levels are lowered, but gets upregulated in the functionally fit βν null adult muscle subsets. The results suggest, βν might function as a modulatory component of the integrin network rather than an essential determinant of IFM development. These findings uncover distinct yet cooperative functions of βPS and βν in Drosophila muscle development, providing a framework to understand how integrin diversity contributes to muscle performance.

Keywords:  Drosophila; Integrin; Muscle function; βPS; βν

DOI:  https://doi.org/10.1016/j.gene.2026.150350
J Cell Mol Med. 2026 Aug;30(16): e71289

An Ultrastructural and Proteomic Analysis in DM1 Young Adults' Myoblasts: Stressed RER and Mitochondrial Dysfunction Involvement.

Renata Del Carratore, Alessandra Falleni, Margherita Bernardeschi, Giada Frenzilli, Michela Ripolone, Sabrina Salani, Filippo Geraci, Fabiana Miraglia, Cristina Del Seppia.

  Myotonic dystrophy type 1 (DM1) is a progressive muscular disorder caused by the expansion of CTG repeats in the 3' UTR of the DMPK gene. Although the pathogenic mechanisms remain unclear, recent evidence suggests that activation of innate immune responses may contribute to disease progression. In this study, we examined the ultrastructure and proteomic data of myoblasts from young adult DM1 patients carrying approximately 800 and 1300 CTG repeats in order to investigate a link between cellular stress and immune activation. We observed activation of the type I interferon (IFN-I) pathway associated with rough endoplasmic reticulum stress (sRER). The sRER response is likely triggered by the accumulation of toxic RNA species generated from the expanded DMPK allele. Our data suggest that this inappropriate activation of the IFN-I pathway contributes to muscle pathology, not by blocking differentiation directly, but through chronic stress signalling. These findings support a model in which innate immune dysregulation plays a central role in DM1 muscle degeneration and highlight the IFN1 pathway as a potential therapeutic target for restoring normal muscle function.

Keywords:  dsRNA; interferon I signalling; mitochondrial dysfunction; myotonic dystrophy type 1; proteomics; stressed RER

DOI:  https://doi.org/10.1111/jcmm.71289
Cell Rep Med. 2026 Aug 13. pii: S2666-3791(26)00405-2. [Epub ahead of print] 102988

Exercise intensity modulates interorgan communication and is associated with cardiometabolic health outcomes in humans.

Luke Olsen, Javier Botella, Douglas Barrows, Ethan Romero, Kaitlyn Baird, Mutsumi Katayama, Ece Kilic, Christopher Peralta, Nadège Zanou, Henry Sanford, Laurie Farrell, Christopher L Axelrod, Kaja Plucińska, Jeanne Walker, Lu Yan, Katie Fredrickson, Olivier Pourquie, Jeremy M Robbins, Ekaterina V Vinogradova, Henrik Molina, Nicolas Place, John P Kirwan, Juleen R Zierath, Anna Krook, Robert E Gerszten, David J Bishop, Paul Cohen.

  Exercise is an integral therapy for many cardiometabolic diseases, including obesity, type 2 diabetes, and hypertension. Despite its broad health benefits, the circulating factors that mediate exercise adaptations in humans remain incompletely defined, particularly across different exercise intensities. Here, we conducted a multi-cohort human exercise intervention incorporating sprint-interval exercise (SIE) and moderate-intensity exercise (MIE) to analyze intensity-dependent regulation of interorgan crosstalk. We found that exercise intensity distinctly influenced the plasma proteome and metabolome in untrained and trained participants. By integrating multi-organ gene and protein expression datasets with in vitro and in vivo tissue sampling, we mapped regulated proteins to their predicted tissues of origin and destination. Muscle fibers and adipocytes were particularly sensitive to exercise intensity and observed to undergo broad secretory and transcriptomic changes. Moreover, we leveraged a large-scale plasma-phenome database to identify intensity-dependent proteins associated with cardiometabolic health and disease, highlighting how exercise intensity differentially shapes interorgan communication and organismal health.

Keywords:  exercise; interorgan crosstalk; metabolism; moderate-intensity exercise; physiology; sprint-interval exercise

DOI:  https://doi.org/10.1016/j.xcrm.2026.102988