bims-musmir 2026-02-22 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–02–22
nineteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

The Age-Dependent Resident Myonuclear Multi-Omic Response to an Acute Skeletal Muscle Hypertrophic Stimulus in Mice.
Human neuromuscular organoids mimic cancer-induced muscle cachexia.
Exosomal microRNAs as Central Regulators of Cancer Cachexia: Multi-Omics Insights into Muscle Wasting and Adipose Browning.
Tumor-Derived Polyamines Initiate Fat Wasting in Cancer Cachexia.
The Mislocalization of TDP-43 to Mitochondria Impairs Myotube Maturation.
The role of exosomal miRNA-125b derived from colon cancer-associated fibroblasts in skeletal muscle cachexia.
Characterizing mitochondrial phenotypes and MERCS in aged human skeletal muscle myoblasts.
Loss of Myonuclei and Transcriptional Activity During Diaphragm Atrophy in Critically Ill Patients.
How Acute and Chronic Exercise Regulate Muscle Atrophic Genes to Mitigate Sarcopenia: A Narrative Review.
Gait analysis for functional evaluation in a surgical hindlimb suspension model of muscle atrophy.
PDGFRβ signaling restrains myocyte function to limit the regenerative capacity of skeletal muscle.
Mustn1 ablation in male mice results in fiber type and gene expression alterations during skeletal muscle regeneration.
Interferon-γ-Responsive Microglia-Derived Extracellular Vesicles Inhibited Neurogenesis After Stroke via MicroRNA-199a-5p/SIRT1 Axis.
Neuronal TLR4 upregulation activates the cGAS-STING pathway to induce ferroptosis in EAE mice.
Cross-organ communication based on non-coding RNA networks leads to cognitive dysfunction in mice.
Sarcopenia: An overview of emerging therapies and pathophysiological insights in age-related skeletal muscle decline.
Molecular insight into transcriptome profiling of aerobic exercise induced changes in aged skeletal muscle.
Molecular mechanisms of skeletal muscle fibrosis and potential targeted therapeutic strategies.
Reduced late endosome/lysosome function promotes SLE through chronic PI3k activity and SHP-1/SHIP-1 defects.

Adv Sci (Weinh). 2026 Feb 17. e21633

The Age-Dependent Resident Myonuclear Multi-Omic Response to an Acute Skeletal Muscle Hypertrophic Stimulus in Mice.

Pieter J Koopmans, Ronald G Jones, Ana Regina Cabrera, Francielly Morena, Nicholas P Greene, John J McCarthy, Ahmed Ismaeel, Yuan Wen, Kevin A Murach.

  A detailed analysis of how muscle fiber nuclei (myonuclei) respond to a hypertrophic stimulus could provide a critical step toward understanding compromised skeletal muscle plasticity with age. We used recombination-independent doxycycline-inducible myonucleus-specific fluorescent labelling, tissue RNA-sequencing, myonuclear DNA methylation analysis, multi-omic integration, and single myonucleus RNA-sequencing (smnRNA-seq) to define the molecular characteristics of adult (6-8 month) and aged (24 month) murine skeletal muscle after acute mechanical overload (MOV). In adult and aged MOV muscles, we found that: 1) similarities in the transcriptional response to loading-specifically in metabolism genes - were partly explained by a post-transcriptional microRNA-mediated mechanism that we corroborated using an inducible muscle fiber-specific miR-1 knockout model, 2) differences in age-dependent transcriptional responses were linked to the magnitude and location of differential DNA methylation in resident myonuclei, specifically around genes such as Myc, Runx1, Mybph, Ankrd1, collagen (Col) genes, and minichromosome maintenance (Mcm) genes, 3) adult and aged resident myonuclear transcriptomes had differing enrichment for innervation-related transcripts as well as unique transcriptional profiles in an Atf3+ "sarcomere assembly" population after MOV, and 4) cellular deconvolution analysis and smnRNA-seq supports a role for neuromuscular junction regulation in age-specific hypertrophic adaptation. These data are a roadmap for uncovering molecular targets to enhance aged muscle adaptability.

Keywords:  RNA‐seq; RRBS; aging; overload; smnRNA‐seq

DOI:  https://doi.org/10.1002/advs.202521633
Cell Rep Methods. 2026 Feb 17. pii: S2667-2375(26)00031-7. [Epub ahead of print] 101331

Human neuromuscular organoids mimic cancer-induced muscle cachexia.

Pietro Chiolerio, Beatrice Auletta, Camilla Pezzini, Luigi Sartore, Giorgia Gregolon, Onelia Gagliano, Cecilia Laterza, Valeria Roxana Balmaceda Valdez, Davide Cacchiarelli, Camilla Luni, Carlo Viscomi, Melanie Planque, Sarah-Maria Fendt, Marco Sandri, Roberta Sartori, Anna Urciuolo.

  Cancer cachexia, a devastating metabolic wasting syndrome affecting up to 80% of solid cancer patients, remains incurable despite advances in tumor biology understanding. This study introduces neuromuscular organoids (NMOs) derived from human-induced pluripotent stem cells (hiPSCs) as a platform to investigate cancer-driven muscle cachexia. We found that NMOs respond well to atrophic stimuli and replicate the key features of cancer cachexia when treated with conditioned media derived from cachexia-inducing cancer cells. Specifically, cachectic NMOs showed muscle mass loss, impairment of muscle contraction, alteration of intracellular calcium homeostasis, appearance of mitochondrial dysfunction with a metabolic shift, and enhancement of autophagy. Based on these results, we propose NMOs derived from hiPSCs as an in vitro tool for investigating human muscle cachexia, with potential future avenues of patient-specific modeling and therapeutic screening.

Keywords:  CP: cancer biology; CP: stem cell; autophagy; cancer cachexia; human induced pluripotent stem cells; in vitro human disease model; metabolic remodeling; mitochondrial dysfunction; neuromuscular junction; neuromuscular organoid; skeletal muscle wasting

DOI:  https://doi.org/10.1016/j.crmeth.2026.101331
J Proteome Res. 2026 Feb 18.

Exosomal microRNAs as Central Regulators of Cancer Cachexia: Multi-Omics Insights into Muscle Wasting and Adipose Browning.

Farman Matloob Khan, Raafat El Awady, Shahid Mehmood, Zahid Hussain, Mohd Izani Othman, Abu Bakar Abdul Majeed.

  Cancer cachexia is a multifactorial syndrome marked by involuntary weight loss, skeletal muscle wasting, adipose tissue remodeling, and systemic metabolic dysfunction. Exosome-derived microRNAs (miRNAs) have emerged as key mediators, reprogramming host tissues and driving these hallmarks. However, no integrated framework has linked exosomal miRNAs to the proteomic and metabolomic alterations that characterize cachexia. This review critically synthesizes evidence on exosomal miRNAs in muscle atrophy, adipose browning, and systemic metabolic disruption. Tumor-secreted exosomal miRNAs activate proteolytic pathways (miR-21/29a via TLR7/8NF-κB/JNK), suppress antiapoptotic signals (miR-195a/125b targeting BCL-2), induce ER stress (miR-181a-3p), impair mitochondrial quality control (miR-122), and remodel metabolic signaling (miR-155, miR-183-5p). These mechanisms converge to produce proteomic signatures of enhanced proteolysis, apoptosis, and lipolysis, alongside metabolomic shifts toward amino acid efflux, fatty acid mobilization, and glycolytic inefficiency. This is the first integrated review linking exosomal miRNAs with proteomic and metabolomic signatures of cancer cachexia, offering a multiomics framework for biomarker discovery and therapeutic targeting. We highlight their potential as early biomarkers, therapeutic targets, and modulators of rehabilitation response, while outlining research gaps including limited clinical validation, intertumor heterogeneity, and the need for multiomics integration to advance translation into patient care.

Keywords:  adipose tissue browning; cancer cachexia; exosome-derived microRNAs; metabolomic reprogramming; muscle wasting; proteomic dysregulation

DOI:  https://doi.org/10.1021/acs.jproteome.5c01051
bioRxiv. 2025 Dec 03. pii: 2025.12.01.691597. [Epub ahead of print]

Tumor-Derived Polyamines Initiate Fat Wasting in Cancer Cachexia.

Matias Fabregat, Rachel J Fenske, Julia K Hansen, Cameron J Kaminsky, Jevin Lortie, Alexander Nassar, Kayla Kressin, Annie Jen, Lucia Cilloni, Katherine Overmeyer, Caroline M Alexander, John W Garrett, Perry J Pickhardt, Joshua J Coon, Costas A Lyssiotis, Marina Pasca di Magliano, Lingjun Li, Adam J Kuchnia, Andrea Galmozzi.

Cancer-associated cachexia (CC) is a fatal metabolic condition characterized by progressive loss of fat and muscle mass, yet its early molecular drivers remain poorly defined. Here, we identify a polyamine-dependent tumor-adipose crosstalk that triggers adipocyte lipolysis and fat wasting during the pre-cachexia stage, preceding systemic inflammation and muscle atrophy. Cancer-derived polyamines are enriched in extracellular vesicles and promote lipid mobilization via eIF5A hypusination, independent of adrenergic signaling. In preclinical models, polyamine accumulation associates with early fat loss and elevated circulating fatty acids. Clinically, automated CT imaging of newly diagnosed pancreatic cancer patients reveals increased adipose density, reflecting lipolysis, that correlates with circulating polyamine levels and predicts poor survival. These findings support polyamine metabolism as a mechanistic driver and candidate biomarker of early cachexia, providing a framework for early detection and targeted intervention.

DOI: https://doi.org/10.64898/2025.12.01.691597
FASEB J. 2026 Feb 28. 40(4): e71603

The Mislocalization of TDP-43 to Mitochondria Impairs Myotube Maturation.

Yalan Wan, Zhen Yu, Juan Yang, Wei Zhang, Meng Yu, Lingchao Meng, Zhaoxia Wang, Yun Yuan, Linhao Ruan, Jianwen Deng, Peng Wang.

  Aggregation of TDP-43 in neuronal cells is a defining neuropathological hallmark of amyotrophic lateral sclerosis (ALS). Emerging evidence suggests that TDP-43 pathology also occurs in skeletal muscle fibers, but its functional significance in myocytes remains poorly understood. In this study, we utilized the C2C12 myoblast cell to investigate the subcellular localization of TDP-43 during myogenic differentiation. Our findings demonstrate that TDP-43 progressively translocates to mitochondria in parallel with myotube maturation. Notably, increased mitochondrial localization of TDP-43 was also observed in skeletal muscle tissues from patients with ALS, corroborating the clinical relevance of this phenomenon. Functional assays revealed that inhibition of TDP-43 mitochondrial translocation significantly enhances myotube maturation. Collectively, these results support a pathophysiological role for aberrant mitochondrial mislocalization of TDP-43 in regulating myogenic differentiation and contributing to muscle degeneration in TDP-43 proteinopathies.

Keywords:  TDP‐43; amyotrophic lateral sclerosis; mitochondria; myotube maturation

DOI:  https://doi.org/10.1096/fj.202504624R
PLoS One. 2026 ;21(2): e0342052

The role of exosomal miRNA-125b derived from colon cancer-associated fibroblasts in skeletal muscle cachexia.

Ho Seung Kim, Jinsu Kim, Bom Lee, Yonghyun Lee, So-Yeon Park, Bo-Young Oh, Kyung-Ah Cho, Soon Sup Chung, Gyoung Tae Noh.

Cancer-associated cachexia is a multifactorial syndrome characterized by significant weight loss, primarily due to skeletal muscle atrophy. This condition impairs the quality of life and survival of patients with cancer. Although the mechanisms underlying cancer-associated cachexia, including exosomes and microRNAs (miRNAs), have been extensively explored, research specifically focusing on cancer-associated fibroblast (CAF)-derived exosomes is lacking. Therefore, in this study, we evaluated the effects of CAF-derived exosomal miRNAs from colon cancer on skeletal muscles using the Human Skeletal Muscle (HSkM) cell line. CAF-derived exosomes were isolated from colon cancer samples, and their effects on cell morphology were analyzed using confocal microscopy. The results indicate that treatment with CAF-derived exosomes significantly reduced myosin diameter. Moreover, miRNA sequencing revealed that miR-125b was enriched in CAF-derived exosomes. HSkM cells were subsequently transfected with a miR-125b mimic, which significantly reduced myosin diameter. Notably, co-treatment with CAF-derived exosomes and an miR-125b inhibitor reversed this effect. In conclusion, this study demonstrates the potential role of CAF-derived exosomes and miR-125b in cancer-associated cachexia, offering insights into the contribution of the tumor microenvironment and suggesting possible therapeutic targets.

DOI: https://doi.org/10.1371/journal.pone.0342052
PLoS One. 2026 ;21(2): e0343604

Characterizing mitochondrial phenotypes and MERCS in aged human skeletal muscle myoblasts.

Yufu Unten, Kazuaki Takafuji, Yumiko Masukagami, Isshin Shiiba, Keigo Horiuchi, Filip Husnik, Shigeru Yanagi, Norifumi Tateishi, Toshihide Suzuki.

Age-associated declines in skeletal muscle function are linked to cellular senescence and mitochondrial alterations, yet mitochondrial phenotypes in aged human myoblasts remain insufficiently characterized. Here, we examined primary skeletal muscle myoblasts from young and elderly donors to assess mitochondrial function, morphology, and mitochondria-endoplasmic reticulum (ER) contact sites (MERCS). Myoblasts from older donors exhibited senescence features, including elevated SA-β-gal activity and reduced Lamin B1 expression, accompanied by increased mitochondrial oxidative stress. Despite marked mitochondrial hyperfusion and increased mitochondrial DNA content, mitochondrial oxygen consumption rate and membrane potential per mitochondrial area were comparable between young and old cells. MERCS were significantly elevated in aged myoblasts and were reduced by scavenging mitochondrial reactive oxygen species (mtROS), indicating an association between oxidative stress and MERCS formation. These findings suggest that mitochondrial hyperfusion and enhanced MERCS accompany cellular aging in human myoblasts and may contribute to maintaining mitochondrial function under elevated oxidative stress.

DOI: https://doi.org/10.1371/journal.pone.0343604
J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70228

Loss of Myonuclei and Transcriptional Activity During Diaphragm Atrophy in Critically Ill Patients.

Wout J Claassen, Marloes van den Berg, Zhong Hua Shi, Rianne J Baelde, Sylvia Bogaards, Luuk Bonis, Heleen Hakkeling, Arezou Bamyani, Gerben J Schaaf, Albertus Beishuizen, Chris Dickhoff, Reinier A Boon, Leo Heunks, Tyler J Kirby, Coen A C Ottenheijm.

   BACKGROUND: Diaphragm weakness frequently develops in critically ill patients and is explained by a combination of atrophy and myofiber dysfunction. Myofibers are large syncytial cells maintained by a population of myonuclei, which provide gene transcripts to a finite fiber volume, termed the myonuclear domain. Myonuclear number is a determinant of transcriptional capacity and therefore critical for diaphragm and peripheral muscle regeneration after critical illness. Changes in myonuclear number in myofibers undergoing atrophy have not been investigated in mechanically ventilated ICU patients, but they are of potential clinical importance. Our objective was to investigate if and how myonuclear number changes in the diaphragm of mechanically ventilated ICU patients and whether changes are associated with myofiber atrophy and clinical parameters.
METHODS: We used a combination of transcriptomics, immunohistochemistry and confocal microscopy to study myonuclear alterations in the diaphragm and quadriceps biopsies from mechanically ventilated ICU patients (n = 24) and non-critically ill patients (n = 10).
RESULTS: Compared to control patients, myonuclear number and myonuclear domain were reduced in critically ill patients with diaphragm myofiber atrophy (n = 14) (myonuclear number per mm of 133 [92-183] vs. 92 [83-105], p = 0.03 (slow myofibers) and 149 [118-189] vs. 88 [69-109], p = 0.004 (fast myofibers); myonuclear domain size was 44 [34-51] vs. 29 pL, p = 0.004 (slow myofibers) and 41 [39-48] vs. 27 pL, p = 0.001 (fast myofibers) of control patients and ICU patients with atrophy, respectively). Increased intrinsic apoptotic pathway activation was identified as a mechanism underlying myonuclear removal (percentage of apoptotic myonuclei of 0.64 [0.60-0.84] and 0.95 [0.84-1.2], p = 0.015 and increased percentage of activated caspase-3 positive myonuclei of 2,5 [1.6-3.3] vs. 5.7 [4.3-11], p = 0.001 in control patients and ICU patients with atrophy, respectively). Total transcriptional activity in myofibers decreased with myonuclear loss (RNA-Pol-2 Ser5 fluorescence intensity per fibre of 2.6 [2.2-3.3] vs. 5.8 [3.1-6.7] AU, p = 0.036 in control patients and ICU patients with atrophy, respectively). Furthermore, muscle stem cell number was reduced in the patients with diaphragm atrophy (PAX7 positive nuclei per myofiber of 0.10 [0.09-0.11] vs. 0.05 [0.04-0.07], p = 0.002 in control patients and ICU patients with atrophy, respectively). No correlation was found between myonuclear loss and duration or mode of mechanical ventilation.
CONCLUSIONS: We identified myonuclear loss due to intrinsic apoptotic pathway activation as a potential mechanism underlying diaphragm atrophy in mechanically ventilated patients. The loss of myonuclei may contribute to impaired regeneration of myofibers after critical illness. Duration and mode of mechanical ventilation are not the major drivers of these modifications.

Keywords:  critical care; diaphragm weakness; mechanical ventilation

DOI:  https://doi.org/10.1002/jcsm.70228
Sports Med. 2026 Feb 14.

How Acute and Chronic Exercise Regulate Muscle Atrophic Genes to Mitigate Sarcopenia: A Narrative Review.

Maysa Vieira de Sousa, Diana Bento da Silva Soares, Hassane Zouhal, Anthony C Hackney, Juan Del Coso, Samuel Katsuyuki Shinjo.

Muscle atrophy is defined as the reduction in muscle mass and strength resulting from a decrease in muscle fiber size and protein content. Muscle atrophy may result from physical inactivity, aging, starvation, or extended periods of limb immobilization. In addition, there are clinical conditions that are intrinsically associated with progressive muscle wasting, such as cancer, diabetes, or chronic heart failure, among others, as these conditions often involve a catabolic hormonal status or a decrease in neuromuscular stimulation. Overall, muscle atrophy leads to significant loss of health and quality of life as it reduces the independence and mobility of individuals affected by this disorder. Physical inactivity is the most common cause of muscle atrophy, especially in older adults, as it increases inflammation factors (TNF-α, IL-1β, and IL-6) and glucocorticoid levels (e.g., cortisol), disrupts intracellular signaling (GH/IGF-1, testosterone, and myostatin), and triggers decreased signaling of growth factors, such as diminished phosphorylation of FoxO by Akt. As a result of this decreased signaling, FoxO translocates to the nucleus of the muscle cell and induces the expression of muscle atrophy-related genes such as ATROGIN-1 (formally designated as FBXO3, also known as MAFbx) and MuRF-1 (formally designated as TRIM-63, also known as IRF). The higher expression of the proteins encoded by these genes, Atrogin-1 and MuRF-1, activates the ubiquitin-proteasome system in the striated muscle tissue responsible for degrading and recycling damaged, misfolded, or unneeded proteins. Therefore, the lack of muscle activity due to prolonged physical inactivity leads to muscle protein degradation and ultimately to muscle wasting. In the elderly and other populations with clinical conditions, there is a progressive reduction in physical activity and changes in food intake that may accelerate the loss of muscle mass and function, as well as increase body fat, giving rise to the phenomenon of sarcopenia. These changes in body composition increase the risk of suffering from chronic diseases, with a clear impact on progressively reduced mobility and increased risk of falls. Acute and chronic exercise can partially interrupt this vicious cycle in older adults and sedentary populations with chronic diseases, as it can diminish muscle wasting by activating molecular mechanisms to enhance muscle growth. Specifically, exercise can enhance muscle protein synthesis by activating the mTOR pathway while reducing protein degradation by suppressing the expression of muscle atrophy genes. In this narrative review, we summarize the mechanisms of action of the genes associated with muscle atrophy, MuRF-1 and ATROGIN-1, and their differential expression patterns following experimental and clinical trials involving chronic and acute exercise exposure, along with other potential regulators implicated in muscle remodeling.

DOI: https://doi.org/10.1007/s40279-025-02383-3
J Physiol. 2026 Feb 17.

Gait analysis for functional evaluation in a surgical hindlimb suspension model of muscle atrophy.

Yanping Xu, Zhentao Zhang, Peng Chen, Natalie Kellon, Ashley He, Usman Alizai, Sunjoon Lee, Keerthika Sathish, Zhiyu Yan, Xinyu Zhou, Laura Kutz, Diamantis I Tsilimigras, Timothy M Pawlik, Hua Zhu.

  Disuse-induced skeletal muscle atrophy, commonly resulting from bedrest, immobilisation or spaceflight, leads to rapid loss of muscle mass and impaired mobility. Although muscle mass and contractile force are standard assessments in experimental models, these measures often fail to capture neuromuscular co-ordination deficits essential for effective movement. To better characterise these deficits, we employed a mouse hindlimb suspension (HLS) model for 14 days to induce disuse atrophy, confirmed by reductions in muscle mass, fibre type remodelling and satellite cell depletion, all of which were only partially reversed after a 7-day reloading period. In vivo analysis showed that gastrocnemius contractile force was significantly reduced following HLS and recovered incompletely after reloading. To functionally assess mobility, we implemented a non-invasive treadmill-based gait analysis, which revealed domain-specific impairments across neural control/rhythm, neuromuscular co-ordination and stability/variability, which were only partially restored after reloading, whereas muscle strength-related metrics such as paw drag showed mild but consistent alterations. At the molecular level, we identified elevated expression of MG29, subcellular redistribution of MG53 and altered expression of neuromuscular function-related genes (e.g. Ninj1, Prkg1, Ryr1 and S100a1), suggesting that MG29 and MG53 may contribute to impaired muscle plasticity and synaptic remodelling. Overall, our findings demonstrate that gait analysis can enhance the functional assessment of muscle disuse and recovery, offering a translational tool to evaluate interventions targeting atrophy-related mobility decline. KEY POINTS: Hindlimb suspension induces muscle atrophy and contractile loss, but functional consequences are not fully captured by traditional measurements. Gait analysis provides a non-invasive framework to evaluate neuromuscular performance across four domains: muscle strength/size, neural control/rhythm, neuromuscular co-ordination and stability/variability. Hindlimb suspension caused domain-specific impairments in rhythm control, co-ordination and stability, which were only partially restored after reloading, whereas strength-related metrics such as paw drag showed mild but consistent alterations. Correlation analyses revealed parallel reductions in propulsion- and rhythm-related gait metrics alongside decreases in muscle fibre size and tetanic force, indicating a functional-structural linkage between gait output and muscle integrity. Functional impairment is associated with satellite cell loss, MG29 upregulation, MG53 redistribution and neuromuscular function-related gene alteration. These findings identify gait metrics as biomarkers that may serve as early, non-invasive indicators of muscle disuse and recovery, providing mechanistic insights and a new tool to evaluate interventions targeting atrophy-related mobility loss.

Keywords:  gait analysis; hindlimb suspension; mitsugumin 29; mitsugumin 53; muscle atrophy

DOI:  https://doi.org/10.1113/JP289401
J Clin Invest. 2026 Feb 16. pii: e188272. [Epub ahead of print]136(4):

PDGFRβ signaling restrains myocyte function to limit the regenerative capacity of skeletal muscle.

Siwen Xue, Abigail M Benvie, Jamie E Blum, Benjamin D Cosgrove, Anna E Thalacker-Mercer, Daniel C Berry.

  Muscle cell fusion is critical for the formation and maintenance of multinucleated myotubes during skeletal muscle development and regeneration. However, the molecular mechanisms directing cell-cell fusion are not fully understood. Here, we identified platelet-derived growth factor receptor β (PDGFRβ) signaling as a key modulator of myocyte function in adult muscle cells. Our findings demonstrated that genetic deletion of Pdgfrb enhanced muscle regeneration and increased myofiber size, whereas Pdgfrb activation impaired muscle repair. Inhibition of PDGFRβ activity promoted myonuclear accretion in both mouse and human myotubes, whereas PDGFRβ activation stalled myotube development by preventing cell spreading to limit fusion potential. Furthermore, PDGFRβ activity cooperated with TGF-β signaling to regulate myocyte size and fusion. Mechanistically, PDGFRβ signaling required STAT1 activation, and blocking STAT1 phosphorylation enhanced myofiber repair and size during regeneration. Collectively, PDGFRβ signaling acts as a regenerative checkpoint and represents a potential clinical target to improve skeletal muscle repair.

Keywords:  Adult stem cells; Development; Muscle biology; Signal transduction; Skeletal muscle

DOI:  https://doi.org/10.1172/JCI188272
Physiol Rep. 2026 Feb;14(4): e70772

Mustn1 ablation in male mice results in fiber type and gene expression alterations during skeletal muscle regeneration.

Kaitlin Tagliaferri, Nithya Thomas, Michael Atallah, Stavroula Triantafillou, Michael Hadjiargyrou.

  We previously developed a Mustn1 conditional knockout (KO) mouse model targeting Pax7-expressing skeletal muscle satellite cells and showed its role in glucose metabolism, strength, gait, peak contractile strength, and myofiber composition. To investigate Mustn1's role in muscle regeneration, we used these KO mice in a cardiotoxin (CTX)-induced tibialis anterior injury model. Despite no major histological differences or deficits in ladder climbing between KO and wild-type (WT) mice at post-injury (Day 2-10), we observed significant shifts in fiber type composition. Mustn1 KO mice had more Type IIa fibers at Day 5, while Type IIx and IIb fibers were reduced at Day 2 and 10, respectively. Additionally, we observed increases in Type I fiber cross-sectional area in the Mustn1 KO mice at Day 0 and 2. Lower numbers of centrally nucleated fibers were also seen in the Mustn1 KO mice at Day 10. Pax7+ cells were also greater in numbers in the Mustn1 KO mice at Day 2 and 10. Lastly, expression of myogenic genes also differed significantly between the two strains. These data suggest that Mustn1 is integral to skeletal muscle fiber composition and myogenic gene expression thereby facilitating muscle repair and regeneration.

Keywords:  Mustn1; cardiotoxin; fiber‐type; regeneration; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.70772
J Am Heart Assoc. 2026 Feb 20. e043532

Interferon-γ-Responsive Microglia-Derived Extracellular Vesicles Inhibited Neurogenesis After Stroke via MicroRNA-199a-5p/SIRT1 Axis.

Tongtong Xu, Dongliang Qian, Shiyu Deng, Yiyan Guo, Hanlai Li, Yanqin Geng, Lin Gan, Qianyuan Lian, Jingjing Xu, Huaitong Yao, Jing Ye, Enkhbat Myagmartsend, Wanlu Li, Zhijun Zhang, Guo-Yuan Yang, Jixian Wang, Yaohui Tang, Qingzhu An.

   BACKGROUND: Previous studies have reported the presence of interferon-responsive microglia in the brain after central nervous system injury. However, their roles and the underlying mechanisms in neurological function recovery remain poorly understood.
METHODS: Adult male mice were subjected to 90-minute transient middle cerebral artery occlusion, and brain tissues were analyzed using single-cell RNA sequencing (scRNA-seq) at 14 days after stroke. Immunostaining, quantitative real-time polymerase chain reaction and ELISA were conducted to validate the presence of interferon-γ-responsive microglia in stroke mice brains. Extracellular vesicles (EVs) were isolated from interferon-γ-treated BV2 microglia via ultracentrifugation. Interferon-γ EVs were then used to treat neural stem cells (NSCs) in vitro or administered intravenously to mice every other day, starting at 7 days after transient middle cerebral artery occlusion. Neurobehavioral tests, cresyl violet staining, Golgi staining, and immunostaining were performed to evaluate NSC differentiation, neurogenesis, and neurobehavioral recovery. Micro RNA (miR) sequencing and bioinformatic analysis were conducted to explore targeted genes and signaling pathways underlying interferon-γ EV-mediated inhibition of neurogenesis.
RESULTS: Single-cell RNA sequencing, immunostaining, quantitative real-time polymerase chain reaction, and ELISA showed the presence of interferon-γ-responsive microglia in stroke mice brains. Interferon-γ EVs were internalized by NSCs, leading to reduced NSC survival and neuronal differentiation. Administration of interferon-γ EVs increased brain atrophy volume, inhibited neurobehavioral recovery and neurogenesis in mice after stroke. miRNA array revealed 12 upregulated microRNAs, and treatment with miR-199a-5p mimic inhibited the survival and neuronal differentiation of NSCs, and knockdown of miR-199a-5p in interferon-γ EVs increased neurogenesis in stroke mice. miRNA database analysis and luciferase reporter assay identified SIRT1 as a downstream target gene of miR-199a-5p. Treatment with SIRT1 agonist promoted the survival and neuronal differentiation of NSCs, confirming that interferon-γ EVs inhibited neurogenesis via miR-199a-5p/SIRT1.
CONCLUSIONS: Our study demonstrated that interferon-γ EVs inhibited the survival and neuronal differentiation of NSCs, exacerbating brain injury via the miR-199a-5p/SIRT1 axis after ischemic stroke, providing a novel target for treating ischemic stroke.

Keywords:  extracellular vesicles; interferon‐γ–responsive microglia; neurogenesis; stroke

DOI:  https://doi.org/10.1161/JAHA.125.043532
Int Immunopharmacol. 2026 Feb 16. pii: S1567-5769(26)00208-0. [Epub ahead of print]174 116364

Neuronal TLR4 upregulation activates the cGAS-STING pathway to induce ferroptosis in EAE mice.

Hongzhuo Qin, Lingfei Yang, Jingjie Du, Xiaomeng Xu, Ziyi Chen, Qingsheng Li, Yudi Xu, Mengyao Li, Yanfei Li, Yanjie Jia.

   INTRODUCTION: Progressive neurofunctional impairment in multiple sclerosis (MS) is largely driven by neuronal damage and loss, yet the underlying molecular mechanisms remain poorly understood. This study aimed to investigate the role of neuronal Toll-like receptor 4 (TLR4) in promoting ferroptosis, an iron-dependent cell death pathway, during experimental autoimmune encephalomyelitis (EAE).
METHODS: We leveraged a MOG35-55-induced EAE mouse model (n = 10 per group) alongside in vitro LPS-stimulated SH-SY5Y mono- and co-culture systems (n = 3 biological replicates) to interrogate the crosstalk between TLR4 signaling and ferroptosis. This link was comprehensively evaluated via biochemical assays, Western blotting, RT-qPCR, co-immunoprecipitation, immunofluorescence analyses, and transmission electron microscopy. Furthermore, we mechanistically dissected the underlying signaling cascades using siRNA-mediated gene silencing and co-immunoprecipitation.
RESULTS: Both in vivo and in vitro models recapitulated classical ferroptosis features, including NCOA4-mediated ferritinophagy, lipid peroxidation, and iron overload. Mechanistically, we suggest that neuronal TLR4 activation may provoke the release of mitochondrial DNA into the cytosol, thereby potentially engaging the cGAS-STING axis and precipitating dysregulated iron metabolism. Observations indicate that the TLR4 signaling contributes to ferroptosis even within the complex inflammatory microenvironment of microglia-neuron co-cultures. In EAE mice, pharmacological blockade of ferroptosis via Liproxstatin-1 appeared to ameliorate clinical severity, associated with restored neuronal GPX4 expression in the brain and spinal cord, and concomitantly suppressed lipid peroxidation.
DISCUSSION: This study proposes a specific TLR4-mtDNA-cGAS-STING-NCOA4 signaling cascade that may facilitate neuronal ferroptosis in EAE mice. These findings suggest a novel mechanism of neuronal injury in MS and underscore that targeting this intrinsic neuronal pathway could represent a promising therapeutic strategy to ameliorate progressive neurodegeneration.

Keywords:  Cyclic GMP-AMP synthase; Ferroptosis; Multiple sclerosis; Stimulator of interferon genes; Toll-like receptor 4

DOI:  https://doi.org/10.1016/j.intimp.2026.116364
Neurobiol Dis. 2026 Feb 13. pii: S0969-9961(26)00063-X. [Epub ahead of print]221 107319

Cross-organ communication based on non-coding RNA networks leads to cognitive dysfunction in mice.

Heiko Dunkel, Lars R Jensen, Franziska Sperling, Jonah Schreier, Oliver von Bohlen Und Halbach, Faruq M Hossain, Stefan Simm, Andreas W Kuss.

   BACKGROUND: Beyond regulation of mRNAs by individual ncRNA types, like miRNAs, circRNAs or lncRNAs, their interplay as competitive endogenous RNAs (ceRNAs) appears pivotal in diseases. ceRNAs are promising biomarkers in diagnosing diseases as well as in understanding off-target drug mechanisms or developing specific therapeutics. Many diseases are influenced at different molecular levels and across multiple organs, making cross-organ multi-omics interaction studies necessary to holistically understand diseases and their regulation. In our study we applied this approach to the cognitive dysfunction caused by deficiency of functioning tRNA 2'-O-methyltransferase FTSJ1. We investigated the expression changes of mRNA and multiple ncRNA species (miRNAs, lncRNAs, circRNAs) in Ftsj1-deficient versus wild-type C57BL/6 J mice and constructed organ-specific ceRNA networks for the brain, heart, kidney, liver, spleen. Validation of potential ncRNA biomarkers was performed using degradome sequencing as well as qRT-PCR.
RESULTS: The strongest effects of differential expression due to Ftsj1 deficiency were observed in liver and kidney, where especially genes involved in fatty acid metabolism showed altered expression. We reveal a prominent ceRNA network induced by Ftsj1 deficiency in liver and kidney, mediated by four hub-miRNAs (miR-378d, miR-3076-5p, miR-3474, miR-296-3p) enriched with acyl-CoA-related genes, including Acly, Acss2, and Mvk. In contrast, brain tissues showed minimal changes in gene expression, hinting at cross-organ interactions for cognitive dysfunction also supported by previously described phenotypes like muscle weakness in mice with Ftsj1 deficiency.
CONCLUSIONS: Our results suggest the involvement of multiple cross-organ regulatory mechanisms for single gene-associated intellectual disability. For FTSJ1 deficiency, this indicates that the cognitive impairment presented by affected human individuals can be associated with metabolic impairment and ceRNA crosstalk along the liver-brain and kidney-brain axes. Our findings provide a new perspective on the development of cognitive impairments caused by mutations of individual genes and underline the importance of multi-omics cross-organ analyses for the development of therapeutics and identification of biomarkers based on ceRNA-mediated networks.

Keywords:  Cognitive disability; Differential expression analysis; Ftsj1; Multi-omics; Multi-organ axes; ceRNA networks; circRNA; lncRNA; miRNA; ncRNA target prediction

DOI:  https://doi.org/10.1016/j.nbd.2026.107319
Biochem Pharmacol. 2026 Feb 18. pii: S0006-2952(26)00144-9. [Epub ahead of print] 117813

Sarcopenia: An overview of emerging therapies and pathophysiological insights in age-related skeletal muscle decline.

Deepak Mishra, Lucy Mohapatra.

  Sarcopenia is characterized by an age-associated decline of skeletal muscle mass and function. It has been recognized as a clinical disease by the World Health Organization since 2016. This condition is commonly linked with signs of physical frailty, functional limitations, higher frequency of falls, increased hospitalization, and a rise in mortality rates, and it is gaining recognition as a crucial geriatric syndrome considering the increasing life expectancy and the growing elderly population worldwide. A few pathological mechanisms of sarcopenia have been identified, even though its etiologies are still unclear. These mechanisms include cellular senescence, oxidative stress, and apoptosis along with "inflammaging. It also involves changes in the types of muscle fibers, satellite cells, mitochondrial function, myokines, and inflammatory cytokines in aged sarcopenic muscle as compared with young or healthy aged muscles. Ultimately, this review explores new therapeutic avenues for the management of sarcopenia. There is not a well-recognized treatment for sarcopenia clinically now. However, there are a variety of pharmacological and non-pharmacological approaches that have been used to manage sarcopenia. Among the non-pharmacological interventions, diverse exercise protocols are supplemented by potent nutritional components. Exercise mimetics, myokines and monoclonal antibodies, nicotinamide adenine dinucleotide (NAD+) stimulators, mitochondrial boosters, and compounds that regulate muscular apoptosis are all included in the pharmacological interventions. This consolidated body of knowledge is expected to enhance the formulation of more effective therapeutic strategies aimed at maintaining muscle mass in the elderly population, thus fostering the independence of senior individuals and mitigating the socioeconomic challenges related to sarcopenia.

Keywords:  Aging; Apoptosis; Exercise; Inflammation; Mitochondria; Muscles; Myokines; Sarcopenia

DOI:  https://doi.org/10.1016/j.bcp.2026.117813
NPJ Aging. 2026 Feb 18.

Molecular insight into transcriptome profiling of aerobic exercise induced changes in aged skeletal muscle.

Masroor Anwar, Priyajit Kaur, Dinesh Gupta, Avinash Chakrawarty, A B Dey, Sharmistha Dey.

Skeletal muscle aging causes loss of both muscle mss and strength, often leading to sarcopenia. Clinical manifestation of sarcopenia has been found to improve with exercise intervention. The molecular mechanisms in response to exercise intervention in aged skeletal muscles are not fully understood. We performed transcriptomic profiling of aged animal model with exercise intervention for identifying the plausible mechanism leading to enhanced muscle function. Expression levels of 43,629 RNAs were analyzed for the process of aging and exercise intervention. Differentially expressed genes showed 22,196 protein-coding and 21,433 non-coding RNAs that were found to be significantly altered with intervention. Genes associated with extracellular matrix and inflammatory responses exhibited significant change with intervention. Slpi (Secretory Leukocyte Protease Inhibitor)- a vital gene in the intervention group with its role as an inflammatory regulator and tissue repair gene. The activation of quisqualate receptor, neurotransmitter receptors and postsynaptic signal transmission pathways were most relevant for upregulated genes in the intervention group. Downregulated genes in the intervention group were mostly associated with ATP-dependent protein disaggregase activity. Our study provides a comprehensive analysis of the global transcriptome that governs aerobic exercise induced changes in aged muscle leading to compensatory adaptation with exercise in aged model group.

DOI: https://doi.org/10.1038/s41514-026-00336-2
Front Immunol. 2026 ;17 1714238

Molecular mechanisms of skeletal muscle fibrosis and potential targeted therapeutic strategies.

Jiahuan Gong, Jingxuan Xu, Jitai Zhang, Yuntian Shen, Hualin Sun, Bingqian Chen.

  Skeletal muscle fibrosis is a pathological process characterized by excessive deposition of extracellular matrix (ECM). It commonly occurs in various diseases such as muscular dystrophy, aging, cancer cachexia, and muscle injury. This condition leads to destruction of muscle structure, loss of function, and impaired regeneration, significantly affecting patients' quality of life. This review systematically summarizes the molecular mechanisms underlying skeletal muscle fibrosis. Key signaling pathways include transforming growth factor-beta (TGF-β)/Smad, yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ), inflammation and immune regulation, oxidative stress, and microRNA-mediated regulation. The roles of fibro/adipogenic progenitors (FAPs), macrophages, and myofibroblasts in this process are also discussed. Among these, the TGF-β/Smad pathway acts as a central driver of fibrosis by promoting the differentiation of FAPs into myofibroblasts and stimulating ECM synthesis. YAP/TAZ integrates mechanical and biochemical signals, further amplifying the fibrotic response. Inflammation, oxidative stress, and epigenetic regulators such as miRNAs and lncRNAs also contribute through complex networks. Regarding therapeutic strategies, this article highlights various interventions including pharmacological inhibition (e.g., TGF-β inhibitors, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEIs/ARBs), antioxidants), gene- and RNA-targeting therapies (e.g., miRNA mimics or inhibitors), cell-based therapies (e.g., Mesenchymal Stem Cells (MSCs)), biological agents (e.g., anti-connective tissue growth factor (CTGF) antibodies), as well as physical and nutritional interventions (e.g., electroacupuncture, magnetic stimulation, natural compounds). These approaches demonstrate strong anti-fibrotic potential by modulating ECM metabolism, the immune microenvironment, and cellular behaviors. However, current research still faces challenges such as disease heterogeneity, optimal treatment timing, drug delivery issues, and long-term safety concerns. Therefore, future studies should focus on developing highly specific targeted therapies, integrating multi-omics technologies and imaging assessments, and advancing personalized combination strategies to ultimately achieve effective prevention and treatment of skeletal muscle fibrosis.

Keywords:  FAPs; TGF-β; YAP/TAZ; anti-fibrotic therapy; skeletal muscle fibrosis

DOI:  https://doi.org/10.3389/fimmu.2026.1714238
JCI Insight. 2026 Feb 10. pii: e191767. [Epub ahead of print]

Reduced late endosome/lysosome function promotes SLE through chronic PI3k activity and SHP-1/SHIP-1 defects.

SunAh Kang, Andrew J Monteith, Liubov Arbeeva, Karissa Grier, Shruti Saxena Beem, Anthony C Trujillo, Xinyun Bi, Kai Sun, Rebecca E Sadun, Mithu Maheswaranathan, Megan Eb Clowse, Saira Z Sheikh, Jennifer L Rogers, Barbara J Vilen.

  Degradation of cellular waste from phagocytosis, endocytosis and autophagy occurs through hydrolases that become activated during acidification of late endosomes and lysosomes (LELs). In a cross-sectional study we show diminished LEL acidification and the accumulation of surface-bound nucleosome on monocytes, dendritic cells, and B cells from SLE patients. Diminished acidification and exocytosis of undegraded IgG-ICs is evident in active, but not inactive disease. This is supported by our murine study where LEL acidification is diminished, promoting exocytosis and the accumulation of cell surface IgG-immune complexes. Mechanistically, LEL dysfunction is induced by chronic PI3k activation in lupus-prone MRL/lpr mice. We also show that on a non-autoimmune C57BL/6 background, deficiency in SHP-1 and inhibition of SHIP-1 activity is sufficient to recapitulate LEL dysfunction found in MRL/lpr mice. Non-acidic LELs are evident in 67% of patients, and associate with SLEDAI arthritis, rash, and nephritis. The high frequency of LEL dysfunction in SLE suggests it could serve as a biomarker identifying a specific disease endotype.

Keywords:  Autoimmune diseases; Autoimmunity; Immunology; Lupus; Lysosomes

DOI:  https://doi.org/10.1172/jci.insight.191767