bims-musmir 2026-10-04 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–10–04
eleven papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Tumor-derived SAA1-TLR4 signaling drives tumor-to-muscle communication in pancreatic cancer cachexia.
Mitochondrial membrane lipid cardiolipin controls fiber-type adaptations in aging muscle via estrogen-related receptor γ.
Spatial Transcriptomics Identifies Muscle Inflammation Susceptibility as a Distinct Periarticular Skeletal Muscle Phenotype in End-Stage Knee Osteoarthritis.
Myogenic differentiation-derived small extracellular vesicles as a therapeutic strategy for miR-193b-3p-mediated muscle regeneration.
A TBK1/ULK1 signalling axis couples lysosomal stress to TFEB activation.
Neuromuscular junction formation by compartmentalized culture using human iPS cell-derived motor neurons and skeletal muscle cells.
Pathogenic mutations in ATAD3A cause dysregulation of RagC/D-TFEB axis and disrupt lysosomal homeostasis.
Acid Stress-induced plasma membrane ceramide arises from lysosome-plasma membrane fusion.
Lysophospholipase PNPLA7 is a critical checkpoint of phosphatidylcholine catabolism and turnover for skeletal muscle homeostasis.
Integrative Nanopore and Illumina sequencing reveals age-associated tRNA modification and CCA-tail dynamics in yeast.
Temporal control of mitochondrial mutagenesis reveals the fate of mtDNA mutations with age.

bioRxiv. 2026 Sep 09. pii: 2026.09.04.748998. [Epub ahead of print]

Tumor-derived SAA1-TLR4 signaling drives tumor-to-muscle communication in pancreatic cancer cachexia.

Gabriele Guarnaccia, Jimmy Massenet, Alessandra Cecchini, Elena Guarnaccia, Beatrice Silvestri, Chiara Nicoletti, Jesus R Barajas, David Sala, Marcos G Teneche, Brightany Li, Luca Caputo, Cedomir Stamenkovic, Tatiana M Moreno, Rabi Murad, Shawn Delaware, Daphne Mayer, Yijuan Zhang, Priyanka Gupta, Alexandre R Colas, Alessandro Vasciaveo, Caroline Kumsta, Peter D Adams, Will Wang, Cesare Gargioli, Commisso Cosimo, Pier Lorenzo Puri, Alessandra Sacco.

Cancer cachexia limits treatment tolerance and survival in pancreatic ductal adenocarcinoma (PDAC), yet the tumor-derived signals driving tissue dysfunction remain poorly understood. Here, we identify serum amyloid A1 (SAA1) as a mediator of tumor- to-host communication acting through Toll-like receptor 4 (TLR4). Tumor-derived SAA1 was elevated in human PDAC and in a mouse PDAC model and disrupted both myofiber and muscle stem cell (MuSC) homeostasis. Genetic reduction of tumor-derived SAA1 uncoupled tumor progression from host wasting, preserving muscle mass and function and prolonging survival without affecting primary tumor growth. Mechanistically, SAA1-TLR4 signaling drove multicellular remodeling of the skeletal muscle microenvironment. Therapeutic TLR4 inhibition after cachexia onset restored muscle mass, function and MuSC abundance and prolonged survival independently of tumor growth. Conservation of SAA1-TLR4 signaling in human skeletal muscle identifies a therapeutically actionable tumor-host pathway and demonstrates that host deterioration can be targeted independently of tumor progression.

DOI: https://doi.org/10.64898/2026.09.04.748998
Nat Aging. 2026 Sep 29.

Mitochondrial membrane lipid cardiolipin controls fiber-type adaptations in aging muscle via estrogen-related receptor γ.

Fabian Finger, Mikkel Frost, Shinya Watanabe, Tao Ma, Taewook Kang, Dipsikha Biswas, Ruben Zapata-Perez, Vincent Anton, Lucile Dollet, Lasse K Markussen, Nanami Senoo, Iuliia Karavaeva, Astrid Linde Basse, Oksana Dmytriyeva, Tara TeSlaa, Jesper F Havelund, Amy M Ehrlich, Marta Moreno-Torres, Caio Yogi Yonamine, Nicoline R Andersen, Ida Blom, Francisco Garcia-Carrizo, Piyarat Siripoksup, Magnus Asping, Thomas S Nielsen, Marcus Nygård, Anders B Klein, Andrey Tvardovskiy, Trine S Nicolaisen, Carlos Durantez-Fernández, Klaus Qvortrup, Clara Prats, Joshua D Rabinowitz, Christoffer Clemmensen, Lykke Sylow, Juleen R Zierath, Jonas T Treebak, Tim J Schulz, Trisha J Grevengoed, Steven M Claypool, Julien Prudent, Rob C I Wüst, Susanne Mandrup, Riekelt H Houtkooper, Kei Sakamoto, Nils J Færgeman, Martin R Larsen, Katsuhiko Funai, Steen Larsen, Zachary Gerhart-Hines.

Aging paradoxically leads to both a decline in skeletal muscle mitochondrial function and a shift in muscle composition that favors fibers rich in mitochondria. Yet the biological rationale and mechanism underlying this phenomenon remain largely unknown. Here we show that synthesis of the mitochondrial membrane lipid, cardiolipin, causally links mitochondrial dysfunction to fiber-type adaptations in aging mouse and human skeletal muscle. By mimicking the aging decline of skeletal muscle cardiolipin levels in young mice using inducible tissue-specific cardiolipin synthase 1 (Crls1) deletion, we could reproduce key aging hallmarks, including the shift from glycolytic to oxidative fibers. This shift is mediated by mitochondria-to-nucleus signaling through the nuclear receptor, estrogen-related receptor γ, which promotes reactive oxygen species-sensitive glucose uptake and enhanced glycolytic rerouting to sustain antioxidant defenses. Restoring Crls1 expression in adult Crls1 knockout mice reestablishes cardiolipin levels, initiates reversal of muscle atrophy and fully rescues premature mortality. These findings reveal how changes in a mitochondrial membrane lipid cell autonomously orchestrate fiber-type adaptations in aging and myopathies.

DOI: https://doi.org/10.1038/s43587-026-01227-7
bioRxiv. 2026 Sep 22. pii: 2026.09.16.752138. [Epub ahead of print]

Spatial Transcriptomics Identifies Muscle Inflammation Susceptibility as a Distinct Periarticular Skeletal Muscle Phenotype in End-Stage Knee Osteoarthritis.

Franccesco P Boeno, Zachary A Graham, Qi Su, Michael J Stec, Arny A Ferrando, Wei Keat Lim, Marcas M Bamman.

Skeletal muscle dysfunction is a major contributor to disability and incomplete functional recovery in patients with end-stage knee osteoarthritis (KOA), yet the spatial components of disease-associated molecular remodeling remain poorly understood. Here, we applied spatial transcriptomics to paired skeletal muscle biopsies obtained from the surgical (Sx) and contralateral (Ct) limbs of individuals undergoing total knee arthroplasty (TKA) to define the cellular architecture of periarticular muscle and determine how muscle inflammation susceptibility (MuIS) shapes local transcriptional programs. Integrated analysis of 27,087 spots obtained from 22 muscle histological cross-sections (11 Sx-Ct pairs) revealed seven spatially resolved transcriptional domains corresponding to slow and fast myofiber states, an extracellular matrix/fibroadipogenic-enriched domain, a pericyte/smooth muscle domain, and a satellite cell/myogenic-enriched domain. Despite advanced unilateral disease, the major annotated cellular compartments were similarly represented between Sx and Ct limbs. KOA-associated remodeling was reflected primarily by within-cluster transcriptional changes, with the most informative differences observed in fibroadipogenic, pericyte/smooth muscle, and satellite/myogenic domains. Within Sx, MuIS stratification identified a coordinated transcriptional program characterized by denervation-and regeneration-associated genes and altered contractile and metabolic features. Neighborhood analysis localized denervation-associated signals primarily to fast-myofiber-rich regions, while local adjacency patterns among the examined myofiber, fibroadipogenic, and pericyte/smooth muscle domains were broadly preserved. Our findings provide the first spatial transcriptomic analysis of periarticular skeletal muscle in end-stage KOA and identify MuIS as a distinct local transcriptional phenotype in diseased muscle.

DOI: https://doi.org/10.64898/2026.09.16.752138
Mol Ther Nucleic Acids. 2026 Dec 08. 37(4): 103087

Myogenic differentiation-derived small extracellular vesicles as a therapeutic strategy for miR-193b-3p-mediated muscle regeneration.

Sujin Choi, Min-Ji Sung, Hyun-Ju An, Soonchul Lee.

  The regeneration of skeletal muscle involves precisely regulated intercellular communication, including extracellular vesicle (EV)-mediated processes. In this study, we show that during in vitro myogenic differentiation of human skeletal muscle progenitor cells (myoblasts), miR-193b-3p accumulates within small EVs (sEVs) in a temporally regulated manner. Both sEV-mediated and synthetic delivery of miR-193b-3p enhanced myogenic differentiation in vitro and promoted histological recovery in a murine volumetric muscle loss model. Mechanistically, we demonstrate that miR-193b-3p directly suppresses adapter-related protein complex 2 subunit mu 1 (AP2M1), a clathrin-associated adapter protein that has not been well characterized in muscle biology, and identify it as a negative regulator of myogenic progression. AP2M1 knockdown phenocopied the effects of miR-193b-3p, suggesting that this regulatory axis may contribute to muscle regeneration. In addition, transcriptomic analyses of aged rodent and sarcopenic human datasets revealed conserved upregulation of AP2M1 in degenerative muscle states, supporting its potential clinical relevance. Collectively, these findings reveal a myogenic differentiation-dependent, sEV-mediated miRNA regulatory mechanism that contributes to muscle regeneration. Based on these results, we propose the miR-193b-3p-AP2M1 axis as a potential therapeutic target for muscle-wasting disorders.

Keywords:  AP2M1; MT: Non-coding RNAs; extracellular vesicles; miR-193b-3p; myogenesis

DOI:  https://doi.org/10.1016/j.omtn.2026.103087
Nature. 2026 Sep 30.

A TBK1/ULK1 signalling axis couples lysosomal stress to TFEB activation.

Alessandra Esposito, Ibrahim Bayramoglu, Chiara Varriale, Maria Pia Cavaliere, Maria Elsa Brunetti, Rossella Agostinis, Rachel M Jansen, Dan A Tudorica, Yongjia Duan, Martina Spacci, Alessia Calcagnì, Carolin D Strobl, Verena Passerini, Fabrizio Andreone, Jlenia Monfregola, Julia Richter, Francesca Sacco, Wolfram Klapper, Oliver Weigert, Andrea Ballabio, Roberto Zoncu, James H Hurley, Joern Dengjel, Gennaro Napolitano.

Lysosomal adaptation to environmental changes is critical for cellular and metabolic homeostasis and requires coordination by the mTORC1 kinase, which conveys nutritional and stress signals into distinct, substrate-specific outputs1,2. The FLCN-FNIP complex (FLCN:FNIP) serves as a crucial regulator of lysosomal function by selectively controlling the ability of mTORC1 to inhibit transcription factor EB (TFEB), a master regulator of catabolic programs and a known oncogene3. Yet how FLCN:FNIP activity is regulated has remained unclear. Here we identify a nutrient-independent lysosomal signalling pathway that regulates FLCN through v-ATPase-driven recruitment of TBK1 or ULK1 (TBK1/ULK1) to lysosomes, via the TAX1BP1 adaptor. This enables TBK1/ULK1-mediated FNIP1 phosphorylation at S296, resulting in inhibition of FLCN and nuclear translocation of TFEB. Recurrent ATP6V1B2 v-ATPase mutations, found in patients with follicular lymphoma, constitutively activate this pathway, leading to hyperactivation of TFEB and follicular lymphoma proliferation. Our work uncovers a lysosomal signalling pathway that is critical for lysosomal adaptation and tumorigenesis.

DOI: https://doi.org/10.1038/s41586-026-11093-3
Front Neural Circuits. 2026 ;20 1838276

Neuromuscular junction formation by compartmentalized culture using human iPS cell-derived motor neurons and skeletal muscle cells.

Masayoshi Kamon, Moe Yamashita, SokeLee Siew, Shuji Wakatsuki, Toshiyuki Araki.

  The neuromuscular junction (NMJ) is a synapse that connects the nerve terminal of a motor neuron to a skeletal muscle fiber. The mechanisms underlying NMJ formation have been elucidated primarily through studies in animal models. However, elucidation of the pathophysiological mechanisms of human neuromuscular diseases and identification of potential therapeutic agents require the establishment of a human NMJ model. In this study, we established a human NMJ model using a compartmentalized culture system with cells derived from human induced pluripotent stem (iPS) cells, which enables quantitative and reproducible assessment of NMJ formation. During extended NMJ culture, morphological changes in the NMJ were observed, along with alterations in the expression of genes related to NMJ and skeletal muscle development, suggesting progressive NMJ maturation. The functionality of the formed NMJs was also confirmed using fluorescent live-cell imaging. These findings suggest that this human NMJ culture model may be applicable for investigating the pathological mechanisms of human neuromuscular diseases and exploring therapeutic agents.

Keywords:  MyoD; culture modeling; imaging; induced pluripoten stem cell; motor neuron (MN); neuromuscular junction (NMJ); skeletal muscle cell (SMC); synaptogeneisis

DOI:  https://doi.org/10.3389/fncir.2026.1838276
bioRxiv. 2026 Sep 25. pii: 2026.09.23.753918. [Epub ahead of print]

Pathogenic mutations in ATAD3A cause dysregulation of RagC/D-TFEB axis and disrupt lysosomal homeostasis.

Mathew B McDougal, Abigail Sandoval, Mike Kinter, Antrix Jain, Sukyeong Lee, Sung Yun Jung, Wan Hee Yoon.

We previously discovered that a de novo variant p.R528W in ATAD3A , encoding a mitochondrial membrane-anchored protein, causes a human neurological syndrome. While ATAD3A mutations induce aberrant lysosomal expansion accompanied by undigested material in the lysosomes, how mutant ATAD3A disrupts lysosomal homeostasis and whether this contributes to neurodevelopmental defects remain unknown. Here we show that pathogenic ATAD3A p.R528W expression disrupts the mTORC1-TFEB axis as revealed by dysregulation of mTORC1 substrate phosphorylation, TFEB nuclear localization, and CLEAR gene activation associated with lysosomal biogenesis. ATAD3A binds to lysosome-localized Rag C/D GTPases, which constitute a platform for TFEB recruitment, with pathogenic variants increasing this association and thereby decreasing lysosomal localization of Rag GTPases. Importantly, overexpression of RagC or RagD restores TFEB phosphorylation in human cells expressing p.R528W, and RagC- D overexpression or TFEB/Mitf knockdown rescues lysosomal expansion and neurodevelopmental defects in Drosophila . These data indicate that disrupted Rag GTPase recruitment to lysosomes and subsequent aberrant TFEB/Mitf activation contribute to neurodevelopmental and lysosomal phenotypes caused by pathogenic mutations in ATAD3A . Our work reveals a novel role for the mitochondrial resident protein ATAD3A in modulating lysosomal homeostasis through regulation of the mTORC1-TFEB axis, providing a mechanistic link between impaired mitochondrial and lysosomal homeostasis in a neurodevelopmental disorder.

DOI: https://doi.org/10.64898/2026.09.23.753918
bioRxiv. 2026 Sep 22. pii: 2026.09.21.753246. [Epub ahead of print]

Acid Stress-induced plasma membrane ceramide arises from lysosome-plasma membrane fusion.

Abhay Kanodia, Anne Ostermeyer-Fay, Maria Hernandez-Corbacho, Ryan Chacon, Mehdi Damaghi, Yusuf A Hannun, Daniel Canals.

Plasma membrane ceramide (PMCer) is a recognized cellular signal that regulates stress responses, such as chemotherapy and membrane damage, triggering apoptosis and plasma membrane repair. Acid sphingomyelinase (ASM) has been proposed to generate PMCer by directly hydrolyzing plasma membrane sphingomyelin into ceramide. However, the enzymatic requirements of ASM are difficult to reconcile with the extracellular environment on the outer leaflet of the plasma membrane. Here, we identify several cellular stress inducers, with acidic stress yielding a stronger response in PMCer generation. Using this inducer, we defined a lysosome-to-plasma membrane pathway for stress-induced PMCer generation. Acidic stress increased PMCer in an ASM-dependent manner, whereas ASM loss or catalytic inactivation abolished this response. Although secreted ASM was enzymatically active when tested in vitro, neither secreted nor exogenous recombinant ASM generated PMCer. Instead, acidic stress induced lysosomal exocytosis, while disruption of lysosomal fusion reduced PMCer accumulation. Modulating lysosomal ceramide translated into PMCer, showing that lysosomal ceramide is directly transferred into the plasma membrane. These findings redefine stress-related PMCer signaling through lysosomal ceramide exocytosis.

DOI: https://doi.org/10.64898/2026.09.21.753246
Cell Rep. 2026 Sep 30. pii: S2211-1247(26)01081-8. [Epub ahead of print] 118003

Lysophospholipase PNPLA7 is a critical checkpoint of phosphatidylcholine catabolism and turnover for skeletal muscle homeostasis.

Shoya Matsumoto, Heeyoon Seo, Yoshitaka Taketomi, Takayoshi Higashi, Yuki Nagasaki, Hiroyasu Sato, Mai Kawaguchi, Yasumasa Nishito, Jonguk Park, Kenji Mizuguchi, Koji Hosomi, Jun Kunisawa, Kaori Saito, Keiko Kato, Tomoyoshi Soga, Tetsuya Hirabayashi, Sumito Ogawa, Makoto Murakami.

  Current evidence suggests that disturbed phosphatidylcholine (PC) turnover causes skeletal muscle dysfunction. However, the enzyme that converts lysophosphatidylcholine (LPC) to glycerophosphocholine (GPC), an irreversible checkpoint in PC catabolism, in skeletal muscle has remained unidentified. Here we show that PNPLA7, a patatin-like phospholipase isoform, is responsible for this process. Pnpla7 deletion in myoblasts impedes the conversion of LPC to GPC and then to choline. Quadriceps muscles in global Pnpla7-deficient mice display thinner muscle fibers with aberrant mitochondrial morphology, reduced endurance capacity, and decreased expression of genes related to fatty acid β-oxidation, mitochondrial functions, and slow-twitch fibers with age. These abnormalities are preceded by alterations in phospholipid composition, with decreases in docosahexaenoic acid-containing PC and mitochondrial cardiolipin. Moreover, skeletal muscle-specific Pnpla7 deficiency results in muscle phenotypes similar to its global deficiency. Identification of the lysophospholipase PNPLA7 aids further understanding of the role of PC turnover in skeletal muscle homeostasis.

Keywords:  CP: metabolism; choline; docosahexaenoic acid; lipidomics; lysophospholipase; mitochondria; patatin-like phospholipase; phosphatidylcholine; phospholipid; skeletal muscle

DOI:  https://doi.org/10.1016/j.celrep.2026.118003
bioRxiv. 2026 Sep 27. pii: 2026.09.22.753482. [Epub ahead of print]

Integrative Nanopore and Illumina sequencing reveals age-associated tRNA modification and CCA-tail dynamics in yeast.

Katherine M Brazell, Christopher Prevost, Natalia Zawrotna, Carrie K Smith, Lindsey N Power, Jeffrey S Smith, Zhangli Su.

Aging is characterized by a progressive loss of proteostasis. Transfer RNAs (tRNAs) are essential regulators of translation, yet their dynamics during aging remain poorly understood due to challenges in sequencing highly modified RNAs. Here we present a benchmarked Nanopore direct RNA sequencing (RNA004 chemistry) resource that profiles the Saccharomyces cerevisiae tRNAome during replicative aging at single-molecule resolution. Using in vitro transcribed tRNA controls, we establish modification detection thresholds and validate key findings with orthogonal Illumina sequencing. While overall tRNA abundance remains largely stable, our resource reveals age-associated terminal A cleavage at the 3' CCA tail of mature tRNAs, targeted T-loop and anticodon modification changes, and single-molecule evidence of modification co-occurrence. This dataset provides a resource for exploring tRNA regulation, translation fidelity, and longevity.

DOI: https://doi.org/10.64898/2026.09.22.753482
bioRxiv. 2026 Sep 27. pii: 2026.09.24.754271. [Epub ahead of print]

Temporal control of mitochondrial mutagenesis reveals the fate of mtDNA mutations with age.

Sarah Jean Shemtov, Eric Hwang, Claire S Chung, Herbert Anson, Lucy Carrillo, Sangmin Lee, Ivetta Vorobyova, Junxiang Wan, Scott R Kennedy, Amy R Vandiver, Bert M Verheijen, Whitaker Cohn, Bérénice A Benayoun, Max A Thorwald, Pinchas Cohen, Jonathan Wanagat, Jean-François Gout, Marc Vermulst.

Mutations in the mitochondrial genome (mtDNA) play a critical role in the aging process and a wide variety of age-related diseases. However, it remains unclear when the mutations that drive physiological decline arise. To answer this question, we generated a new mouse model in which mitochondrial mutagenesis can be confined to a defined window of time. Surprisingly, we found that mutations that arise during the first two months of life are sufficient to drive a wide variety of age-related pathologies, and that the severity of this pathology is broadly regulated by distinct, tissue-specific selective pressures that control the fate of mtDNA mutations with age. Further, we found that selection against deleterious variants can be modulated by manipulation of mitochondrial fusion in vitro and in vivo. These observations raise the possibility that in some tissues, the pace of aging is pre-determined by events that occur early in life and that interventions targeting mitochondrial fusion may be able to slow down or reverse the expansion of these pathogenic variants. These results carry far-reaching implications for strategies aimed at preventing or delaying age-related decline.

DOI: https://doi.org/10.64898/2026.09.24.754271