bims-musmir Biomed News
on microRNAs in muscle
Issue of 2025–05–11
seven papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway
  1. The association of mitochondrial morphology and supercomplex redistribution with skeletal muscle oxidative capacity in older adults.
  2. Muscle Wasting in ICU Patients is Multifactorial and Requires Thorough Workup.
  3. Perspectives on the interpretation of mitochondrial responses during skeletal muscle disuse-induced atrophy.
  4. cGAS-STING-NFκB pathway plays a role in burn injury-induced muscle wasting.
  5. The potential of TAOK1 as a new therapeutic target for the treatment of cancer cachexia-associated muscle atrophy.
  6. Muscle peripheral circadian clock drives nocturnal protein degradation via raised Ror/Rev-erb balance and prevents premature sarcopenia.
  7. Signaling balance of MCTs and GPR81 controls lactate-induced metabolic function and cell death in skeletal muscle cells through Ranbp3l/Nfat5 and Atf4.
  1. Physiol Rep. 2025 May;13(9): e70359
    The association of mitochondrial morphology and supercomplex redistribution with skeletal muscle oxidative capacity in older adults.
    Mauricio Castro Sepulveda, Sylviane Lagarrigue, Francesca Amati.
      Skeletal muscle maximal oxidative capacity (ATPmax) is a key component of age-related sarcopenia and muscle health. The contribution of mitochondrial morphology and electron transport chain supercomplex (SC) assemblies to ATPmax has yet to be determined in human muscle. ATPmax measured in vivo by 31phosphorus magnetic resonance spectroscopy in the quadriceps femoris of nine volunteers (65.5 ± 3.3 years old) was correlated with muscle biopsy outcomes before and after 4 months of supervised exercise. Mitochondrial morphology was assessed in electron micrographs, and SCs were measured by blue native gel electrophoresis. In the sedentary conditions, ATPmax was positively associated with complex (C) I and CIII in SC I+III2+IVn and negatively associated with CI and CIII in SC I+III2. Regarding mitochondrial morphology, ATPmax was positively associated with markers of mitochondrial elongation. Exercise training-induced increases in ATPmax were accompanied by mitochondrial elongation and by the redistribution of free complex III. Indicators of mitochondrial elongation were associated with the redistribution of specific complexes to SC I+III2+IVn. Higher skeletal muscle oxidative capacity in older adults is associated with mitochondrial elongation and the redistribution of electron transport chain complexes into higher rank SCs in the same muscle. Further, we provide evidence that mitochondrial elongation favors mitochondrial SC assembly.
    Keywords:  ATPmax; electron transport chain; mitochondrial elongation; respirasome
    DOI:  https://doi.org/10.14814/phy2.70359
  2. Indian J Crit Care Med. 2025 Apr;29(4): 394
    Muscle Wasting in ICU Patients is Multifactorial and Requires Thorough Workup.
    Josef Finsterer, Walter Strobl.
      Finsterer J, Strobl W. Muscle Wasting in ICU Patients is Multifactorial and Requires Thorough Workup. Indian J Crit Care Med 2025;29(4):394.
    Keywords:  Critically ill myopathy; Muscle toxic medications; Muscle ultrasound; Muscle wasting; SOFA score
    DOI:  https://doi.org/10.5005/jp-journals-10071-24829
  3. J Physiol. 2025 May 05.
    Perspectives on the interpretation of mitochondrial responses during skeletal muscle disuse-induced atrophy.
    Luca J Delfinis, Shahrzad Khajehzadehshoushtar, Christopher G R Perry.
      Reductions in skeletal muscle mitochondrial respiration or increases in mitochondrial reactive oxygen species (ROS) are often interpreted as 'mitochondrial dysfunctions'. However, such changes can also occur as intentional programmed responses to stressors. The term 'mitochondrial dysfunction' could therefore consider the net impact of such responses on other cellular functions. In the case of disuse-induced skeletal muscle atrophy, lower mitochondrial respiration, increased ROS and increased mitochondrial-linked apoptosis have been associated with muscle loss. Such observations support hypotheses that mitochondria contribute to atrophy. If true, there are exciting opportunities for exploring therapeutic strategies that prevent such changes in mitochondrial metabolism. These observations might also support alternative hypotheses where mitochondria are intentionally reprogrammed to serve specific purposes, such as a recalibration of ATP supply to reduced ATP demand during disuse. The goal of this review is to describe what is known regarding skeletal muscle mitochondrial functional responses to muscle disuse, as well as to discuss how these foundational discoveries might lead to new directions that determine whether mitochondrial responses to disuse are causal of atrophy or are adaptive in nature. Three critical questions for consideration include: (1) when is a change in mitochondrial function 'dysfunctional'; (2) how might changes in mitochondrial function represent intentional reprogramming to serve specific purposes; and (3) what factors should be considered when constructing experimental designs to determine the role of mitochondrial functional responses to disuse? Understanding when mitochondrial functional remodelling are dysfunctions or adaptive responses could inform new therapeutic approaches to maintain muscle mass during periods of disuse.
    Keywords:  mitochondrial energetics; muscle disuse; skeletal muscle
    DOI:  https://doi.org/10.1113/JP284160
  4. Shock. 2025 Apr 28.
    cGAS-STING-NFκB pathway plays a role in burn injury-induced muscle wasting.
    Fei Xie, Zerong You, Bin Yan, Jiajia Dai, Jinsheng Yang, Shiyu Wang, Hiroki Ogata, Shingo Yasuhara, Ja Jeevendra Martyn.
       BACKGROUND: Muscle wasting (MW) is a ubiquitous and debilitating consequence of major burn injury (BI), leading to both short- and long-term health complications. The cGAS-STING-NFκB pathway is a key mediator of inflammatory responses triggered by infection, cellular stress, and tissue damage. This study investigated whether activation of this pathway contributes to BI-induced MW and whether C176, a STING inhibitor, could mitigate the MW of BI.
    METHODS: Male C57BL/6 J mice received sham or 30% body BI, with or without daily C176 treatment for 14 days. Hindlimb muscles were analyzed at day 7 and 14 for cytokine expression (RT-qPCR, ELISA), immune cell infiltration (immunohistochemistry), cGAS-STING-NFκB signaling, muscle proteolytic proteins evidenced as MuRF1 and atrogin-1 expression (Western blot), and muscle weight. C2C12 cells (a murine skeletal muscle myoblast cell line) were transfected with Raw 264.7 murine macrophage cell-derived mitochondrial DNA (mtDNA) to mimic BI-induced damage-associated molecular pattern inflammation, with and without C176, to assess muscle inflammatory responses.
    RESULTS: C176 treatment mitigated MW (22 % in tibialis, 13 % in gastrocnemius, p < 0.05) and inhibited the cGAS-STING-NFκB pathway in BI mice. It also decreased infiltration of inflammatory cells into muscle and preserved neuromuscular junction integrity in BI mice. In C2C12 cells, C176 suppressed not only LPS- and mtDNA-induced inflammatory cytokine (IL-1β, TNF-α) release but also muscle proteolytic proteins (MuRF1 and atrogin-1) expression.
    CONCLUSIONS: Activation of the cGAS-STING-NFκB pathway contributes to BI-induced MW, and C176 effectively reduces muscle loss by inhibiting this inflammatory signaling pathway.
    Keywords:  burn injury; cGAS-STING-NFκB; inflammatory cytokines; mitochondrial DNA; muscle wasting
    DOI:  https://doi.org/10.1097/SHK.0000000000002613
  5. Pharmacol Res. 2025 May 06. pii: S1043-6618(25)00188-4. [Epub ahead of print] 107763
    The potential of TAOK1 as a new therapeutic target for the treatment of cancer cachexia-associated muscle atrophy.
    Ruiqin Zhang, Nan Li, Ke Yu, Qiongsen Wang, Meng Fan, Xiongwen Zhang, Xuan Liu.
      Cancer cachexia, a multifactorial metabolic syndrome impacts 50-80% cancer patients, is mainly characterized by skeletal muscle atrophy. In this study, we demonstrated that the thousand-and-one amino acid kinase 1 (TAOK1) was activated in both C2C12 myotubes treated with simulated cancer cachexia injuries as well as in muscle tissues of mice inoculated with various types of tumor cells. Results of phosphoproteomic analysis also showed the increase in phosphorylation of TAOK1 in myotubes induced by simulated cancer cachexia injuries. Knockdown of TAOK1 in C2C12 myoblasts resulted in resistance to cancer cachexia-associated myotube atrophy. Comparing the protein expression profiles of C2C12-TAOK1-KO myotubes and that of control myotubes using proteomic analysis found that, TAOK1 knockout resulted in increased expression of muscle-related proteins and decreased expression of proteins related to MAPK pathway and ubiquitin-proteasome system (UPS). Results of Western blotting analysis confirmed the involvement of TAOK1/MAPK/FoxO3/UPS pathway in cancer cachexia-associated myotube atrophy, and suggested that TAOK1 knockout could ameliorate increased protein degradation but not decreased protein synthesis under cancer cachexia. CP43, a synthesized TAOK1 inhibitor, could ameliorate both in vitro myotube atrophy of C2C12 myotubes under simulated cancer cachexia injuries as well as in vivo muscle atrophy of cancer cachexia mice inoculating with C26 colon tumor cells. In conclusion, our study provides evidence that TAOK1 plays critical roles in activation of protein degradation under cancer cachexia thus targeting TAOK1 might be a potential therapy strategy for treatment of cancer cachexia-associated muscle atrophy.
    Keywords:  C2C12 myotubes; MAPK pathway; TAOK1; cancer cachexia; muscle atrophy; tumor-bearing mice; ubiquitin-proteasome system
    DOI:  https://doi.org/10.1016/j.phrs.2025.107763
  6. Proc Natl Acad Sci U S A. 2025 May 13. 122(19): e2422446122
    Muscle peripheral circadian clock drives nocturnal protein degradation via raised Ror/Rev-erb balance and prevents premature sarcopenia.
    Jeffrey J Kelu, Simon M Hughes.
      How central and peripheral circadian clocks regulate protein metabolism and affect tissue mass homeostasis has been unclear. Circadian shifts in the balance between anabolism and catabolism control muscle growth rate in young zebrafish independent of behavioral cycles. Here, we show that the ubiquitin-proteasome system (UPS) and autophagy, which mediate muscle protein degradation, are each upregulated at night under the control of the muscle peripheral clock. Perturbation of the muscle transcriptional molecular clock disrupts nocturnal proteolysis, increases muscle growth measured over 12 h, and compromises muscle function. Mechanistically, the shifting circadian balance of Ror and Rev-erb regulates nocturnal UPS, autophagy, and muscle growth through altered TORC1 activity. Although environmental zeitgebers initially mitigate defects, lifelong muscle clock inhibition reduces muscle size and growth rate, accelerating aging-related loss of muscle mass and function. Circadian misalignment such as shift work, sleep deprivation, or dementia may thus unsettle muscle proteostasis, contributing to muscle wasting and sarcopenia.
    Keywords:  autophagy; circadian clock; mTOR; muscle; proteasome
    DOI:  https://doi.org/10.1073/pnas.2422446122
  7. Cell Signal. 2025 May 01. pii: S0898-6568(25)00265-7. [Epub ahead of print]132 111852
    Signaling balance of MCTs and GPR81 controls lactate-induced metabolic function and cell death in skeletal muscle cells through Ranbp3l/Nfat5 and Atf4.
    Satayuki Matsuhashi, Arthur Choisez, Yidan Xu, Sepideh D Firouzjah, Kentaro Harada, Lingzi Zeng, Shion Osana, Hiroaki Takada, Ryoichi Nagatomi, Joji Kusuyama.
      Lactate, a byproduct of pyruvate in the glycolytic pathway, has been recognized as a signaling molecule and a regulator of gene expression. In skeletal muscles, lactate is dynamically regulated during exercise and influences muscular function, including myogenic differentiation and metabolism. The effects of lactate vary depending on lactate levels, which are influenced by exercise intensity, type, and duration. Furthermore, the effects of lactate on cellular signaling are different during the stages of myogenic differentiation. However, the distribution of lactate signaling in terms of lactate concentration, signaling types, and myogenesis has not been fully elucidated. In this study, we investigated the dual effects of lactate on myogenic differentiation and viability using C2C12 cells and C57BL/6 mice. Low levels of lactate treatment promoted myogenesis in the early stage of C2C12 differentiation, while high lactate concentrations or treatment with 3,5-DHBA, a GPR81 agonist, impaired cell viability during late myogenic differentiation. Transcriptomic analysis and knockdown experiments revealed that lactate promotes myogenesis and muscular metabolic functions through the induction of Ranbp3l and Nfat5 expressions. On the other hand, the detrimental effects of lactate on cell survival are mediated by the GPR81-induced PI3K-Akt/ERK-Atf4 axis. GPR81 signaling also feeds forward the expression of Hcar1 via Akt and ERK. These dual actions of lactate on skeletal muscle were also observed in vivo through lactate or 3,5-DHBA injections and exercise training models. Our study concludes that maintaining a balance in lactate signaling is crucial for regulating skeletal muscle phenotypes in response to exercise and lactate treatments.
    Keywords:  Apoptosis; C2C12; Exercise; Glucose metabolism; Lactate; Lipid metabolism; Myogenesis
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111852
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