bims-musmir 2025-07-13 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2025–07–13
twelve papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Age and sex-specific changes in mitochondrial quality control in skeletal and cardiac muscle.
Scutellarein attenuates cancer cachexia-induced muscle atrophy via targeted inhibition of the JAK/STAT pathway.
Transcriptional Diversity in Response to Aging Across Skeletal Muscles.
Down-regulation of human-specific lncRNA TMEM9B-AS1 in skeletal muscle of people with type 2 diabetes affects ribosomal biogenesis.
Mitochondrial Dysfunction and Defects in Mitochondrial Adaptation to Exercise Training in the Muscle of Patients With COPD: Disease Versus Disuse.
Nucleolar FRG2 lncRNAs inhibit rRNA transcription and cytoplasmic translation, linking FSHD to dysregulation of muscle-specific protein synthesis.
High-Quality Weight Loss in Obesity: Importance of Skeletal Muscle.
Exploring age-related iron dysregulation: effects on longevity, body size, and behavior in C. elegans.
Impact of Adipose Tissue and Lipids on Skeletal Muscle in Sarcopenia.
GDF15: from biomarker to target in cancer cachexia.
Clu1/Clu form mitochondria-associated granules upon metabolic transitions and regulate mitochondrial protein translation via ribosome interactions.
Targeting Dio3 to enhance mitophagy and ameliorate skeletal muscle wasting in sepsis.

Front Aging. 2025 ;6 1606110

Age and sex-specific changes in mitochondrial quality control in skeletal and cardiac muscle.

Catherine B Springer-Sapp, Olayinka Ogbara, Maria Canellas Da Silva, AbryAnna Henderson, Yuan Liu, Steven J Prior, Sarah Kuzmiak-Glancy.

   Introduction: Skeletal and cardiac muscle mitochondria exist in a dynamic reticulum that is maintained by a balance of mitochondrial biogenesis, fusion, fission, and mitophagy. This balance is crucial for adequate ATP production, and alterations in skeletal muscle mitochondria have been implicated in aging-associated declines in mitochondrial function.
Methods: We sought to determine whether age and biological sex affect mitochondrial content [Complex IV (CIV)], biogenesis (PGC-1ɑ), fusion (MFN2, OPA1), fission (DRP1, FIS1), and mitophagy (Parkin, Pink1) markers in skeletal and cardiac muscle by assessing protein expression in tibialis anterior (TA) and ventricular tissue from 16 young (≤6 months) and 16 old (≥20 months) male and female Sprague-Dawley rats.
Results: In the TA, CIV expression was 40% lower in old vs. young rats (p < 0.001), indicating lower mitochondrial content, and coincided with higher expression of Parkin (+4-fold, p < 0.001). Further, MFN2 expression was higher (+2-fold, p < 0.005) and DRP1 expression was lower (-40%, p = 0.014) in older rats. In cardiac muscle, mitochondrial content was maintained in old vs. young rats, and this occurred concomitantly with higher expression of both PGC-1ɑ and Parkin. MFN2 and OPA1 expression were also 1.2-5-fold higher in older rats (p < 0.05 for all). Largely, protein expression did not differ between male and female rats, with the exception of Pink1 and FIS1 expression in the TA.
Discussion: Collectively, older skeletal and cardiac muscle demonstrated higher expression of fusion and mitophagy proteins, which indicates age alters the balance of biogenesis, fission, fusion, and mitophagy. This may, in turn, affect the ability to provide ATP to these metabolically active tissues.

Keywords:  biological sex; fission; fusion; mitophagy; muscle health

DOI:  https://doi.org/10.3389/fragi.2025.1606110
J Adv Res. 2025 Jul 04. pii: S2090-1232(25)00499-0. [Epub ahead of print]

Scutellarein attenuates cancer cachexia-induced muscle atrophy via targeted inhibition of the JAK/STAT pathway.

Heeju Ahn, Heeju Kim, Yeyoung Yoon, Minju Jeong, Sieun Lee, Peng Chen, Keke Wang, Sujung Park, Jae Hwan Kim, Jiyun Ahn, Qiantao Wang, Yoonhee Jin, Young Jin Jang, Sanguine Byun.

   INTRODUCTION: Cancer cachexia is a multifaceted metabolic syndrome characterized by severe loss of skeletal muscle and adipose tissue, diminishing both quality of life and survival in cancer patients. Despite its prevalence, effective treatments for cancer cachexia remain limited. The JAK/STAT signaling pathway has been identified as a key driver of muscle atrophy in cachexia.
OBJECTIVES: This study aimed to investigate the therapeutic potential of scutellarein, a natural compound, as a JAK kinase inhibitor to prevent and mitigate cancer cachexia-induced muscle atrophy.
METHODS: In vitro experiments were conducted using the mouse myoblast cell line C2C12 and human induced pluripotent stem cell (hiPSC)-derived skeletal muscle cells. Myotube atrophy was induced using IFN-γ/TNF-α and cancer cell-conditioned media. Two independent mouse models of cancer cachexia were utilized for in vivo analysis. Muscle tissues were examined through transcriptomic and molecular analyses, including RNA sequencing, PCR, and immunoblotting. Structure-activity relationship studies and molecular docking analyses were performed to investigate the binding interaction of scutellarein with JAK kinases.
RESULTS: Through a chemical library screen, we identified scutellarein as a potent JAK kinase inhibitor. Scutellarein effectively mitigated myotube atrophy by inhibiting protein degradation and promoting protein synthesis in C2C12 and hiPSC-derived muscle cells. In two distinct mouse models of cancer cachexia, scutellarein treatment significantly reduced muscle wasting, improved muscle strength and function, and countered fat depletion. Transcriptomic and molecular analyses of muscle tissues further demonstrated that scutellarein inhibited activation of JAK/STAT pathways and restored suppression of myogenesis and mitochondrial biogenesis. Structure-activity relationship analyses further revealed critical hydroxyl group positions essential for JAK binding.
CONCLUSION: Collectively, our findings suggest scutellarein as a promising candidate for the prevention and treatment of cancer cachexia, providing a novel therapeutic approach to address this critical unmet need in cancer care.

Keywords:  Cancer cachexia; Janus kinase; Muscle atrophy; Scutellarein; Signal transducers and activators of transcription; Skeletal muscle

DOI:  https://doi.org/10.1016/j.jare.2025.07.001
Aging Cell. 2025 Jul 09. e70164

Transcriptional Diversity in Response to Aging Across Skeletal Muscles.

Can Liu, Dongbin Zheng, Rui Zhang, Hong Li, Xingyan Tong, Yujie Wu, Geng Zhang, Siyuan Wang, Hongyu Chen, Zhinong Ren, Ying Sun, Chengdong Wang, Desheng Li, Xuewei Li, Mingzhou Li, Long Jin.

  Aging leads to a gradual decline in muscle function, yet the mechanisms by which different skeletal muscles respond to aging remain unclear. Here, we constructed transcriptional maps of 11 skeletal muscles with extensive transcriptional diversity from young and old mice. Age-related changes in gene expression displayed distinct tissue-specific patterns, involving muscle diseases and metabolic processes. Notably, the mitochondrial-enriched soleus muscle exhibited superior resistance to aging compared to other skeletal muscles. Further, we generated a single-nuclei transcriptomic atlas on representative skeletal muscles, analyzing 73,170 nuclei. We found the age-related changes in the cellular composition of different skeletal muscles and the emergence of new cell states in aged mice. Among different types of myonuclei, type II myonuclei showed particular sensitivity to aging, with reduced metabolic activity of IIb myonuclei with age. We also found cell-specific changes occurring across nonmuscle nuclei populations, including adipocytes, fibro-adipogenic progenitors, and immune cells, accelerating muscle aging and associated pathologies. Intercellular communication analysis revealed more intensive intercellular interactions in aged skeletal muscles, particularly between myonuclei and other cell types. Specifically, we validated the regulatory role of the EGF/EGFR axis in age-related inflammatory processes. These findings provide insight into muscle biology and aging and highlight potential therapeutic targets for age-associated muscle disorders.

Keywords:  EGF/EGFR; aging; myonuclei; skeletal muscles; transcriptional diversity

DOI:  https://doi.org/10.1111/acel.70164
Sci Adv. 2025 Jul 11. 11(28): eads4371

Down-regulation of human-specific lncRNA TMEM9B-AS1 in skeletal muscle of people with type 2 diabetes affects ribosomal biogenesis.

Ilke Sen, Jonathon A B Smith, Elena Caria, Iurii Orlov, Mladen Savikj, Aidan J Brady, Kristian Lian, Stian Ellefsen, Juleen R Zierath, Anna Krook.

Long noncoding RNAs (lncRNAs) are important regulators of skeletal muscle physiology, with altered expression noted in several human diseases including type 2 diabetes. We report that TMEM9B-AS1, a previously uncharacterized lncRNA, is down-regulated in skeletal muscle of men with type 2 diabetes and skeletal muscle from individuals with sarcopenia. Silencing of TMEM9B-AS1 in primary human myotubes attenuated protein synthesis, concomitant with reduced phosphorylation of ribosomal protein S6. Moreover, we show that TMEM9B-AS1 plays a pivotal role in regulation of ribosomal biogenesis by facilitating messenger RNA stabilization of the transcription factor MYC through direct physical interaction with the RNA binding protein, insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1). Disrupted ribosomal biogenesis resulting from TMEM9B-AS1 silencing leads to decreased expression of muscle contractile and structural proteins important for maintenance of skeletal muscle mass and function. Collectively, our data reveal a role of TMEM9B-AS1 in skeletal muscle loss associated with metabolic disorders.

DOI: https://doi.org/10.1126/sciadv.ads4371
Acta Physiol (Oxf). 2025 Aug;241(8): e70079

Mitochondrial Dysfunction and Defects in Mitochondrial Adaptation to Exercise Training in the Muscle of Patients With COPD: Disease Versus Disuse.

Aldjia Abdellaoui, Farés Gouzi, Cécile Notarnicola, Annick Bourret, Amandine Suc, Dalila Laoudj-Chenivesse, Nelly Héraud, Jacques Mercier, Christian Préfaut, Maurice Hayot, Pascal Pomiès.

   AIM: Chronic obstructive pulmonary disease (COPD) is frequently associated with skeletal muscle dysfunction, having a considerable impact on exercise tolerance and patient prognosis. Mitochondria play a role in skeletal muscle weakness and exercise intolerance in COPD, but the majority of studies on mitochondrial function are biased by the fact that physical activity is greater in healthy subjects than in patients. Furthermore, exercise training (ET) has been proposed as a therapeutic strategy to prevent skeletal muscle dysfunction in COPD, but very few results are available on mitochondrial adaptation in response to ET.
METHODS: Skeletal muscle mitochondrial function and the potential efficacy of ET on this function were compared between 12 patients with COPD and 21 healthy subjects with similar low levels of physical activity. Various markers of mitochondrial respiration, oxidative stress, biogenesis, and dynamics were assessed.
RESULTS: Lower oxidative phosphorylation (OxPhos; p < 0.001) and increased nonphosphorylating respiration (p = 0.025) and mitochondrial oxidative damage (lipid peroxidation (p = 0.014) and protein carbonylation (p = 0.020)) were observed in patients. While ET increased OxPhos efficiency (p = 0.011) and reduced nonphosphorylating respiration (p < 0.001) and lipid peroxidation (p < 0.001) in patients' muscle mitochondria, it fails to improve maximal respiration (p = 0.835) and expression of the antioxidant enzyme MnSOD (p = 0.606), mitochondrial transcription factor TFAM (p = 0.246), and mitochondrial complexes I, III, and IV (p = 0.816, p = 0.664, p = 0.888, respectively) as observed in healthy subjects.
CONCLUSION: The mitochondrial dysfunction and the defects in mitochondrial adaptation to ET that we observe in the muscle of patients with COPD are intrinsic to the disease and do not arise from muscle disuse.

Keywords:  COPD; exercise; mitochondrial dysfunction; muscle; oxidative stress; pulmonary rehabilitation

DOI:  https://doi.org/10.1111/apha.70079
Nucleic Acids Res. 2025 Jul 08. pii: gkaf643. [Epub ahead of print]53(13):

Nucleolar FRG2 lncRNAs inhibit rRNA transcription and cytoplasmic translation, linking FSHD to dysregulation of muscle-specific protein synthesis.

Valentina Salsi, Francesca Losi, Bruno Fosso, Marco Ferrarini, Sara Pini, Marcello Manfredi, Gaetano Vattemi, Tiziana Mongini, Lorenzo Maggi, Graziano Pesole, Anthony K Henras, Paul D Kaufman, Brian McStay, Rossella Tupler.

Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary myopathy linked to deletions of the tandemly arrayed D4Z4 macrosatellite at human chromosome 4q35. These deletions cause local chromatin changes and anomalous expression of nearby transcripts FRG2A, DBET, and D4Z4. We discovered that FRG2A is part of a family of long noncoding RNAs (lncRNAs) expressed in skeletal muscle cells, with levels varying among patients. FRG2A localizes in the nucleolus and associates with repetitive DNA at ribosomal DNA (rDNA) loci and centromeres. Elevated FRG2A expression in FSHD cells alters the three-dimensional architecture of heterochromatin at the nucleolar periphery and reduces rDNA transcription and translation rates, resulting in decreased synthesis of skeletal muscle proteins. We also show that myoblasts from FSHD patients display reduced synthesis of skeletal muscle proteins during differentiation. Our results support a disease model in which nucleolar accumulation of D4Z4-driven lncRNA impairs protein synthesis and contributes to muscle wasting.

DOI: https://doi.org/10.1093/nar/gkaf643
Diabetes. 2025 Jul 08. pii: dbi250003. [Epub ahead of print]

High-Quality Weight Loss in Obesity: Importance of Skeletal Muscle.

Mary-Ellen Harper, Robert R M Dent, Ruth McPherson.

ARTICLE HIGHLIGHTS: High-quality weight loss, i.e., a high proportion of fat to skeletal muscle lost during the treatment of obesity, is advantageous for metabolic and physical health. Precise and accurate determinations of skeletal muscle mass in clinical settings are often challenging. In prevention of excessive loss of skeletal muscle during weight loss, advantages include minimization of metabolic adaptation that makes it difficult to sustain weight loss, improved glucose homeostasis and metabolic flexibility, and better mobility and strength. Effective approaches to preserving skeletal muscle include sufficient dietary protein and inclusion of exercise (especially resistance exercise) during weight loss; new pharmacological approaches are under development.

DOI: https://doi.org/10.2337/dbi25-0003
Exp Gerontol. 2025 Jul 03. pii: S0531-5565(25)00155-X. [Epub ahead of print]208 112826

Exploring age-related iron dysregulation: effects on longevity, body size, and behavior in C. elegans.

Rola S Zeidan, Pearl Ebea-Ugwuanyi, Shannon Sykes, Natalia Evripidou, Evelyn Pan, Zachary Markovich, Yi Sheng, Sung Min Han, Christiaan Leeuwenburgh, Rui Xiao.

  Age-related iron accumulation is widely observed in various species and significantly impacts physiological processes. However, systematic investigation into how age-related iron dysregulation affects different life traits is still limited. This study utilizes the model organism C. elegans to examine the roles of iron regulatory genes throughout different life stages, focusing on their effects on iron homeostasis, longevity, mobility, size, and mechanosensation. Our expression analysis indicated that most iron-related genes are generally upregulated by day 15, with some peaking earlier, suggesting their crucial role in mid-life iron regulation. Lifespan assays revealed that certain mutants of non-transferrin bound iron (NTBI) uptake regulators, such as smf-1 and smf-3, are linked to extended lifespans, while zipt-17 mutants showed slightly reduced longevity. Mobility assessments indicated significant declines in speed among several mutant strains by day 7, pointing to mobility issues related to altered iron metabolism. Body size measurements varied considerably among mutant strains, with some demonstrating significant changes over time. Behavioral analyses found that most strains exhibited mechanosensory responses similar to wild-type worms at day 1; however, certain mutants displayed different rates of response reduction by day 7. FerroOrange staining confirmed increased iron accumulation with age in most mutant strains, except for zipt-16 and zipt-17, highlighting the connection between iron regulation and aging. Collectively, our current findings demonstrate that iron regulatory genes in C. elegans play diverse and critical roles in maintaining iron homeostasis, influencing lifespan, mobility, body size, and behavioral responses throughout the organism's life. These findings deepen our understanding of iron regulation's impact on health and aging in C. elegans.

Keywords:  Aging; Behavior; C. elegans; Iron; Mechanosensation; Mobility

DOI:  https://doi.org/10.1016/j.exger.2025.112826
J Cachexia Sarcopenia Muscle. 2025 ;16(4): e70000

Impact of Adipose Tissue and Lipids on Skeletal Muscle in Sarcopenia.

Soo Yeon Jang, Kyung Mook Choi.

   BACKGROUND: Although the decline in muscle mass, function and increased visceral obesity are attracting substantial attention in the ageing society, approved treatment modalities for sarcopenia/sarcopenic obesity (SO) remain limited. Elucidating effects and mechanisms of adipose tissue and lipids on skeletal muscle is important for identifying potential prevention and treatment targets for sarcopenia/SO.
METHODS: In this narrative review, we aim to comprehensively summarize current knowledge on how adipose tissue and lipid metabolites influence skeletal muscle with detailed mechanistic explanations, especially in sarcopenia development. We also tried to explore future perspectives for optimal strategies for managing sarcopenia.
RESULTS: Fatty infiltration in skeletal muscle can alter the structure, metabolism and signalling pathways of muscle, thereby worsening muscle function and physical performance. Intracellular lipid droplets could disrupt normal physiology within muscle cells, but it might be influenced not only by quantity but also by size, location and characteristics of lipid droplets. Intracellular lipid metabolites may induce lipotoxicity in cell signalling of muscle cells, but effects might differ by types or chemical structure. Highly trained athletes exhibit insulin sensitivity despite high levels of muscular fat, a phenomenon called the athlete's paradox. Lipid droplets within the skeletal muscle of athletes are small and are mainly located in the intermyofibrillar area, which is rich in fast-twitch, Type I fibres. In contrast, patients with Type 2 diabetes/obesity accumulate larger lipid droplets in the subsarcolemmal area, which is richer in Type II fibres. Ageing is intricately associated with mitochondrial dysfunction and the concomitant decline in mitochondrial biogenesis, all of which may lead to sarcopenia. SIRT1 and AMPK, two key energy sensors, are involved in mitochondrial biogenesis through regulation of PGC-1α. Modulation of PGC-1α levels in skeletal muscle may help protect against sarcopenia by preserving muscle integrity, enhancing muscle function, improving insulin sensitivity and reducing inflammation and oxidative stress. Excessive nutrient intake and obesity triggers mitochondrial dysfunction by inducing activation of the inflammatory response and increased production of reactive oxygen species. Skeletal muscle and adipose tissue are closely connected through mediators called adipokines and myokines, and it is important to understand the mechanisms of their interaction.
CONCLUSIONS: Dysregulation of lipid metabolism and intramuscular fat accumulation leads to inflammation, oxidative stress, insulin resistance and mitochondrial dysfunction, resulting in reduced muscle mass and strength. Further research on associations between fat/lipids and muscle would be helpful to investigate optimal management strategies for sarcopenia/SO in the rapidly ageing world.

Keywords:  adipose tissue; cachexia; fat mass; lipids; sarcopenia

DOI:  https://doi.org/10.1002/jcsm.70000
Trends Cancer. 2025 Jul 09. pii: S2405-8033(25)00150-5. [Epub ahead of print]

GDF15: from biomarker to target in cancer cachexia.

Max Hüllwegen, Maximilian Kleinert, Stephan von Haehling, Andreas Fischer.

  Most patients with advanced cancer suffer from cachexia, a complex metabolic disorder characterized by unintentional body weight loss that diminishes their quality of life and reduces the effectiveness of therapies. Currently, effective treatments for cachexia remain elusive. Growth differentiation factor 15 (GDF15) is a nonspecific blood biomarker of cancer, hyperemesis gravidarum, and various chronic diseases. GDF15 acts through GDNF family receptor α-like (GFRAL) receptors in the hindbrain to influence food intake, nausea, body weight, and insulin sensitivity. In this review we synthesize the current literature on the role of GDF15 in regulating metabolism and immunosuppression, and elucidate how these processes impact on cancer progression. We highlight recent clinical trials demonstrating that targeting GDF15 can overcome resistance to immunotherapy and increase physical activity, appetite, and weight gain in cancer patients.

Keywords:  GDF15; biomarker; cachexia; cancer; immunosuppression; metabolism

DOI:  https://doi.org/10.1016/j.trecan.2025.06.007
PLoS Genet. 2025 Jul 07. 21(7): e1011773

Clu1/Clu form mitochondria-associated granules upon metabolic transitions and regulate mitochondrial protein translation via ribosome interactions.

Leonor Miller-Fleming, Wing Hei Au, Laura Raik, Pedro Rebelo-Guiomar, Jasper Schmitz, Ha Yoon Cho, Aron Czako, Alexander J Whitworth.

Mitochondria perform essential metabolic functions and respond rapidly to changes in metabolic and stress conditions. As the majority of mitochondrial proteins are nuclear-encoded, intricate post-transcriptional regulation is crucial to enable mitochondria to adapt to changing cellular demands. The eukaryotic Clustered mitochondria protein family has emerged as an important regulator of mitochondrial function during metabolic shifts. Here, we show that the Drosophila melanogaster and Saccharomyces cerevisiae Clu/Clu1 proteins form dynamic, membraneless, mRNA-containing granules adjacent to mitochondria in response to metabolic changes. Yeast Clu1 regulates the translation of a subset of nuclear-encoded mitochondrial proteins by interacting with their mRNAs while these are engaged in translation. We further show that Clu1 regulates translation by interacting with polysomes, independently of whether it is in a diffuse or granular state. Our results demonstrate remarkable functional conservation with other members of the Clustered mitochondria protein family and suggest that Clu/Clu1 granules isolate and concentrate ribosomes engaged in translating their mRNA targets, thus, integrating metabolic signals with the regulation of mitochondrial protein synthesis.

DOI: https://doi.org/10.1371/journal.pgen.1011773
Redox Biol. 2025 Jul 03. pii: S2213-2317(25)00264-2. [Epub ahead of print]85 103751

Targeting Dio3 to enhance mitophagy and ameliorate skeletal muscle wasting in sepsis.

Gang Wang, Ming Chen, Yuheng Zhang, Dacheng Wang, Tao Gao, Jianfeng Duan, Huimin Lu, Minhua Cheng, Yun Xu, Xiaoyao Li, Yan Wang, Ke Cao, Wenkui Yu.

Recent studies highlight the role of skeletal muscle wasting in the sepsis-associated long-term mortality. Despite clinical recommendations for increased protein intake to counteract muscle wasting, the outcomes have been suboptimal, suggesting that anabolic resistance should be considered in addition to nutritional support. Emerging evidence suggests that impaired mitophagy hampers anabolic processes in skeletal muscle, exacerbating muscle wasting in sepsis. Furthermore, thyroid hormone (TH), which is essential for both anabolism and mitophagy, is locally inactivated by type 3 Deiodinase (Dio3) at the onset of sepsis, potentially disrupting mitophagy and contributing to anabolic resistance. Here we demonstrate that local hypothyroidism is a key factor impairing mitophagy in skeletal muscle during early sepsis, leading to metabolic disturbances and muscle wasting. Dio3 knockdown preserves muscle mass, and ameliorates metabolic dysfunction via mitophagy promotion in sepsis models. Mechanistically, the knockdown of Dio3 triggers an upregulation of NRK2, facilitating the restoration of NAD salvage synthesis. This enhancement of NAD levels subsequently activates Sirtuins deacetylase, which in turn decreases PINK1 acetylation, preventing its proteolytic processing by OMA1. Therefore, targeting Dio3 offers a promising therapeutic approach to counteract sepsis-induced muscle wasting.

DOI: https://doi.org/10.1016/j.redox.2025.103751