bims-musmir Biomed News
on microRNAs in muscle
Issue of 2025–11–23
nine papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway
  1. The canonical ER stress IRE1α/XBP1 pathway mediates skeletal muscle wasting during pancreatic cancer cachexia.
  2. Mitochondria transplantation mitigates attenuation of muscle fiber regeneration by evoked contractions.
  3. Mitophagy in skeletal muscle: Impact of ageing, exercise and disuse.
  4. A health-system-scale, episode-resolved multimodal atlas of cancer cachexia.
  5. Amino acid metabolites as potential circulating biomarkers for sarcopenia.
  6. Kenny mediates the recruitment of the phagophore for ubiquitin-dependent mitophagy in Drosophila neurons.
  7. Sequelae and reversal of age-dependent alterations in mitochondrial dynamics via autophagy enhancement in reprogrammed human neurons.
  8. Deletion of fibro-adipogenic progenitors-specific follistatin impairs muscle function and accelerates skeletal muscle atrophy in obese mice.
  9. A unified mechanism for mitochondrial damage sensing in PINK1-Parkin-mediated mitophagy.
  1. EMBO Mol Med. 2025 Nov 17.
    The canonical ER stress IRE1α/XBP1 pathway mediates skeletal muscle wasting during pancreatic cancer cachexia.
    Aniket S Joshi, Meiricris Tomaz da Silva, Anh Tuan Vuong, Bowen Xu, Ravi K Singh, Ashok Kumar.
      Cancer cachexia is a debilitating syndrome characterized by the progressive loss of skeletal muscle mass with or without fat loss. Recent studies have implicated dysregulation of the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) pathways in skeletal muscle under various conditions, including cancer. In this study, we demonstrate that the IRE1α/XBP1 branch of the UPR promotes activation of the ubiquitin-proteasome system, autophagy, JAK-STAT3 signaling, and fatty acid metabolism in the skeletal muscle of the KPC mouse model of pancreatic cancer cachexia. Moreover, we show that the IRE1α/XBP1 pathway is a key contributor to muscle wasting. Skeletal muscle-specific deletion of the XBP1 transcription factor significantly attenuates tumor-induced muscle atrophy. Mechanistically, transcriptionally active XBP1 binds to the promoter regions of genes such as Map1lc3b, Fbxo32, and Il6, which encode proteins known to drive muscle proteolysis. Pharmacological inhibition of IRE1α using 4µ8C in KPC tumor-bearing mice attenuates cachexia-associated molecular changes and improves muscle mass and strength. Collectively, our findings suggest that targeting IRE1α/XBP1 pathway may offer a therapeutic strategy to counteract muscle wasting during pancreatic cancer-induced cachexia.
    Keywords:  ER Stress; Fatty Acid Oxidation; JAK-STAT; Muscle Wasting; Unfolded Protein Response
    DOI:  https://doi.org/10.1038/s44321-025-00337-w
  2. Am J Physiol Cell Physiol. 2025 Nov 19.
    Mitochondria transplantation mitigates attenuation of muscle fiber regeneration by evoked contractions.
    Stephen E Alway, Hector G Paez, Peter J Ferrandi, Christopher R Pitzer, Jessica L Halle, Mohammad Moshahid Khan, Junaith S Mohamed, Michael R Deschenes, James A Carson.
      Rest is generally required for full muscle regeneration after an injury; however, rehabilitative activity is often used after injury to attempt a faster recovery. While rehabilitative activity can enhance muscle regeneration, there is also a risk that returning to vigorous muscle contractions too early after sustaining an injury, could reinjure the muscle, and negatively impact full muscle regeneration. It is not known whether MT added to rehabilitative muscle activity would speed regeneration of muscle morphology more rapidly than resting during the recovery period. Therefore, submaximal electrically evoked isometric contractions (EC) were given to injured muscles of MT treated mice, to test the hypothesis that MT would attenuate the negative regenerative effects of EC and improve the restoration of muscle mass and morphology after muscle injury. Cardiotoxin (CTX) was injected into the tibialis anterior (TA) muscle of one limb of C57BL/6 mice at 8-12 weeks of age to induce muscle injury. Systemic delivery MT or PBS was administered to the mice 48 h after injury. The TA received EC at 40Hz every other day for up to 14-days after CTX injury. While EC-induced mechanical injury slowed muscle repair, muscle fiber regeneration and nuclear domain size was improved by MT. The percentage of collagen and other non-contractile tissue was elevated in CTX-injured and EC treated muscles; however, MT reduced fibrosis/non-contractile tissue deposition in regenerating muscles. Our results provide evidence that systemic mitochondria delivery can improve muscle repair and can attenuate contraction-suppressed muscle fiber regeneration during recovery after injury.
    Keywords:  fibrosis; mitochondria; muscle fiber types; muscle injury; regeneration
    DOI:  https://doi.org/10.1152/ajpcell.00744.2025
  3. Exp Physiol. 2025 Nov 19.
    Mitophagy in skeletal muscle: Impact of ageing, exercise and disuse.
    Anastasiya Kuznyetsova, David A Hood.
      Skeletal muscle plays an important role in whole-body health, quality of life and regulation of metabolism. The maintenance of a healthy mitochondrial pool is imperative for the preservation of skeletal muscle quality and is mediated through mitochondrial quality control consisting of mitochondrial turnover mediated by a balance between organelle synthesis and degradation. The selective tagging and removal of dysfunctional mitochondria is essential for maintaining mitochondrial quality control and is termed mitophagy. The mechanisms of the initial stages of mitophagy involving the recognition and tagging of mitochondria within skeletal muscle are well established, but our understanding of the terminal step involving organelle degradation mediated via lysosomes is in its infancy. An assessment of the proteolytic functions to facilitate the removal and breakdown of dysfunctional mitochondria is crucial for our understanding of the mechanisms of mitophagy, which is essential for maintaining skeletal muscle health. The aim of this review is to address the current knowledge surrounding mitophagy and lysosomal function, alongside distinct physiological conditions, such as ageing, exercise and disuse, that have varying effects on mitophagy and lysosomal adaptations within skeletal muscle.
    Keywords:  Parkin; adaptation; lysosomes; mitophagy; skeletal muscle; transcription factor EB
    DOI:  https://doi.org/10.1113/EP093041
  4. medRxiv. 2025 Sep 30. pii: 2025.09.29.25336906. [Epub ahead of print]
    A health-system-scale, episode-resolved multimodal atlas of cancer cachexia.
    Venise Jan Castillon, Amy X Xie, Sonia Boscenco, Ethan Tse, Neil Ruthen, Jamie Wang, Ziad El Bakouny, Michele Waters, Chenlian Fu, Christopher Fong, Urvi A Shah, A Ari Hakimi, Justin Jee, Eileen White, Tobias Janowitz, Marcus D Goncalves, Ed Reznik.
      Cancer cachexia is a wasting syndrome with outsized impact on morbidity and mortality. Neither the etiology of cachexia, nor its consequences on patient physiology and outcomes, are well-understood. Here, we repurposed longitudinal clinicogenomic data from 59,493 cancer patients to define episode-resolved trajectories of cachexia and linked them to serology, tumor genotypes, and clinical outcomes. Cachexia risk concentrated around periods of disease progression and associated with inferior outcomes in nearly all cancer types. Across cancers, cachectic episodes exhibited a consistent serologic signature characterized by low albumin and hemoglobin and high levels of liver enzymes. Numerous somatic tumor genotypes, including TP53 mutation across several diseases, were associated with elevated cachexia risk. Motivated by these observations, we developed a multivariate model to predict impending risk of cachexia in lung and colorectal cancer patients. Routine clinicogenomic data is therefore a powerful resource for discovery in cachexia and other cancer-associated pathophysiologies.
    DOI:  https://doi.org/10.1101/2025.09.29.25336906
  5. Sci Rep. 2025 Nov 19. 15(1): 40708
    Amino acid metabolites as potential circulating biomarkers for sarcopenia.
    Je Hyun Seo, Jung-Min Koh, Su Jung Kim, Pil Whan Yoon, Won Kim, Sung Jin Bae, Hong-Kyu Kim, Hyun Ju Yoo, Seung Hun Lee.
      Sarcopenia, characterized by the loss of muscle mass and strength, is a multifactorial disorder, including metabolic disturbance. Plasma amino acids (AAs) regulate muscle protein synthesis and breakdown. This study evaluated plasma AA metabolites as potential biomarkers for sarcopenia using metabolomic analysis. We assessed 31 AA metabo lites in an age-matched discovery cohort (72 men, 36 women with sarcopenia; 72 and 36 controls) and a validation cohort (36 men, 46 women with sarcopenia; 128 and 112 controls). In discovery cohort, isoleucine (Ile), leucine (Leu), valine (Val), methionine (Met), phenylalanine (Phe), tryptophan (Trp), alpha-aminoadipic acid (alpha-AAA), glutamate (Glu), and methionine sulfoxide (MetO) were lower in men with sarcopenia, while Glu was lower in women (p < 0.05). Leu in men and Glu in both sexes were associated with skeletal muscle index. A regression model combining Leu and Glu in men and Glu in women yielded an AA score. Adding the AA score to hand grip strength improved the area under the receiver-operating characteristic curve in men (0.646 to 0.767, p = 0.003; 0.563 to 0.767, p = 0.002) and in women (0.486 to 0.728, p < 0.001; 0.576 to 0.680, p = 0.018). Leu in men and Glu in both sexes, reflecting low muscle mass, are potential circulating biomarkers for sarcopenia.
    Keywords:  Aging; Amino acids; Biomarkers; Metabolomics; Sarcopenia
    DOI:  https://doi.org/10.1038/s41598-025-24223-0
  6. Mol Biol Cell. 2025 Nov 19. mbcE25050235
    Kenny mediates the recruitment of the phagophore for ubiquitin-dependent mitophagy in Drosophila neurons.
    Hubert Osei Acheampong, Emily Rozich, Zachary Haupt, Charlee Tokarz, Mousumee Khan, Zahraa A Ghosn, Ryan Insolera.
      The maintenance of healthy mitochondria is essential to neuronal homeostasis. Mitophagy is a critical mechanism that degrades damaged mitochondria, and disruption of this process is associated with neurodegenerative disease. Previous work has shown that mammalian optineurin (OPTN), a gene mutated in familial forms of amyotrophic lateral sclerosis (ALS) and glaucoma, is an adaptor to recruit autophagy machinery to mitochondria for ubiquitin-dependent mitophagy in cultured cells. However, OPTN's role in neuronal mitophagy in vivo remains largely unknown. Here, we demonstrate the Drosophila autophagy adaptor gene Kenny, a homolog of OPTN, mediates the recruitment of the phagophore to mitochondria undergoing ubiquitin-dependent mitophagy. We find that Kenny colocalizes with ubiquitinated mitochondria targeted for autophagic degradation in larval motoneurons, and is concentrated on the mitochondrial surface in areas opposed to the phagophore. Removal of Kenny in conditions of induced mitophagy eliminates the recruitment of the phagophore to ubiquitinated mitochondria and decreases mitophagic flux. In basal conditions, loss of Kenny causes accumulation of ubiquitinated mitochondria in neurons, indicative of stalled mitophagy. These phenotypes were reproduced in Kenny mutants ablating the LC3-interacting region domain. Overall, this work establishes Kenny as a functional homolog of OPTN in flies, and a mediator of neuronal mitophagy in vivo.
    DOI:  https://doi.org/10.1091/mbc.E25-05-0235
  7. bioRxiv. 2025 Oct 02. pii: 2025.10.02.680077. [Epub ahead of print]
    Sequelae and reversal of age-dependent alterations in mitochondrial dynamics via autophagy enhancement in reprogrammed human neurons.
    Eva Klinman, Ji-Sun Kwon, Roland E Dolle, Stephen C Pak, Gary A Silverman, David H Perlmutter, Andrew S Yoo.
      How aging of human neurons affects dynamics of essential organelle such as mitochondria and autophagosomes remains largely unknown. MicroRNA-induced directly reprogrammed neurons (miNs) derived from adult fibroblasts retain age-associated signatures of the donor, enabling the study of age-dependent features in human neurons, including longitudinal isogenic samples. Transcriptomic analysis revealed that neurons derived from elderly individuals are characterized by gene expression changes associated with the regulation of autophagosomes, lysosomes, and mitochondria, compared to young counterparts. To clarify these changes at the cellular level, we performed live-cell imaging of cellular organelles in miNs from donors of different ages. Older donor miNs exhibit decreased mitochondrial membrane potential, which surprisingly co-occurs with a significant increase in mitochondrial fission and fusion events. We posit that the increased fission and fusion of mitochondria may reflect age-dependent compensation for impaired mitochondrial turnover, perhaps due to changes in autophagy. We subsequently identified a significant decrease in autophagosome acidification in neurons derived from individuals >65 years compared to younger donors, and a corresponding age-dependent reduction in neuritic lysosomes resulting in fewer lysosomes available to acidify autophagosomes. This age-dependent deficit in autolysosome flux was rescued by chemically promoting autophagosome generation, which also reversed the age-dependent increase in mitochondrial fission and fusion and improved mitochondrial health. Together, this work reveals a mechanism by which aging reduces autophagic flux secondary to a loss of neuritic lysosomes, resulting in in mitochondria-intrinsic mechanisms to avoid loss of energy production.
    DOI:  https://doi.org/10.1101/2025.10.02.680077
  8. Mol Med. 2025 Nov 21.
    Deletion of fibro-adipogenic progenitors-specific follistatin impairs muscle function and accelerates skeletal muscle atrophy in obese mice.
    Muhammad Rahil Aslam, Muhammad Bilal, Allah Nawaz, Tomonobu Kado, Shinya Abe, Nguyen Quynh Phuong, Memoona, Sana Khalid, Le Duc Anh, Ayumi Nishimura, Yoshiyuki Watanabe, Yoshiko Igarashi, Naeem Iqbal, Maki Yokoyama, Yasuhiro Onogi, Kennichi Hirabayashi, Hiroyuki Miwa, Takumi Era, Martin M Matzuk, Seiji Yamamoto, Koichi Ikuta, Isao Usui, Kohta Kobayashi, Toshihiko Satake, Masaru Kato, Shiho Fujisaka, Kazuyuki Tobe.
       BACKGROUND: Follistatin is a potent regulator of various TGF-β superfamily members, including myostatin (MSTN) and activin A. Previous studies have shown that follistatin is crucial in enhancing myogenesis during acute muscle injury. The mechanism by which fibro-adipogenic progenitors (FAPs)-specific follistatin influences muscle homeostasis in obese mice remains unknown. Therefore, we investigated the physiological role of follistatin in PDGFRα-positive FAPs in the regulation of muscle homeostasis and exercise in obese mice.
    METHODS: A PDGFRα-specific follistatin knockout (follistatin KO) mouse model was generated using PDGFRα-GFP-CreERT2 (PDGFRα-GCE) and follistatinflox/flox mice. These mice were fed a 60% high-fat diet (HFD) for 20 weeks, followed by a series of analyses, including exercise tolerance test, grip strength test, glucose and insulin tolerance assays, gene expression analysis, histology, western blotting, and immunohistochemistry.
    RESULTS: We showed that follistatin KO mice had reduced expression of Fst in skeletal muscle and white adipose tissue. We also showed that follistatin KO mice exhibited decreased exercise performance and altered skeletal homeostasis during obesity. Deletion of follistatin in FAPs activated the MSTN: Activin A/SMADs signaling pathways, which negatively impacted muscle homeostasis. Furthermore, follistatin KO mice showed reduced muscle mass, increased muscle degradation, and atrophic myofibers. Mitochondrial biogenesis, oxidative phosphorylation, and fatty acid oxidation were also altered in the skeletal muscles of follistatin KO mice.
    CONCLUSION: Follistatin plays a protective role in mice by maintaining the metabolic health of skeletal muscles; it restores muscle function during HFD challenge, thereby reducing diet-induced obesity-related complications.
    Keywords:  Exercise capacity; Fibro-adipogenic progenitors (FAPs); Follistatin; Muscle mass; Obesity
    DOI:  https://doi.org/10.1186/s10020-025-01393-1
  9. EMBO J. 2025 Nov 20.
    A unified mechanism for mitochondrial damage sensing in PINK1-Parkin-mediated mitophagy.
    Julia A Thayer, Jennifer D Petersen, Xiaoping Huang, Luiza M Gruel Budet, James Hawrot, Daniel M Ramos, Shiori Sekine, Yan Li, Michael E Ward, Derek P Narendra.
      Damaged mitochondria can be cleared from the cell by mitophagy, using a pathway formed by the recessive Parkinson's disease genes PINK1 and Parkin. Whether the pathway senses diverse forms of mitochondrial damage via a common mechanism, however, remains uncertain. Here, using a novel Parkin reporter in genome-wide screens, we identified that diverse forms of mitochondrial damage converge on loss of mitochondrial membrane potential (MMP) to activate PINK1. Loss of MMP, but not the presequence translocase-associated import motor (PAM), blocked progression of PINK1 import through the translocase of the inner membrane (TIM23), causing it to remain bound to the translocase of the outer membrane (TOM). Ablation of TIM23 was sufficient to arrest PINK1 within TOM, irrespective of MMP. Meanwhile, TOM (including subunit TOMM5) was required for PINK1 retention on the mitochondrial surface. The energy state outside of the mitochondria further modulated the pathway by controlling the rate of new PINK1 synthesis. Together, our findings point to a convergent mechanism of PINK1-Parkin activation by mitochondrial damage: loss of MMP stalls PINK1 import during its transfer from TOM to TIM23.
    Keywords:  Autophagy; Glycolysis; Parkinson’s Disease; Unfolded Protein Response
    DOI:  https://doi.org/10.1038/s44318-025-00604-z
This page is being maintained by Thomas Krichel. It was last updated on 2025‒11‒23 at 16:12.