bims-musmir 2026-03-22 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–03–22
ten papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Phospholipid Glutathione Peroxidase Overexpression Mitigates Cancer Cachexia by Protecting Muscle Mass and Lowering Inflammation.
Deficient Cardiolipin Remodelling Alters Muscle Fibre Composition and Neuromuscular Connectivity in Barth Syndrome.
Impaired Adipose Anabolism in Pancreatic Cancer Cachexia Is Reversed by HuR Inhibition.
Aldh3a1-mediated detoxification of reactive aldehydes contributes to distinct muscle responses to amyotrophic lateral sclerosis progression.
Inhibition of N-Terminal Acetyltransferase C Mitigates Endoplasmic Reticulum Stress-Mediated Muscle Atrophy in Cancer Cachexia.
Tumor-muscle communication in cancer-associated cachexia (Review).
Laminin-α2 is required for the maintenance of the myotendinous junction in vivo.
Characterization of mitochondrial double-stranded RNA levels in Non-Small Cell Lung Carcinoma.
Blood Biochemical Responses to Acute Exercise: Findings from the Molecular Transducers of Physical Activity Consortium (MoTrPAC).
Lysosomal phosphoinositide turnover acts upstream of RagGTPase-mTORC1 and controls muscle growth.

J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70255

Phospholipid Glutathione Peroxidase Overexpression Mitigates Cancer Cachexia by Protecting Muscle Mass and Lowering Inflammation.

Elizabeth Duggan, Jordan D Fuqua, Bo Hagy, Constantin Georgescu, Benjamin F Miller, Holly Van Remmen, Jacob L Brown.

   BACKGROUND: Cancer cachexia is a muscle wasting syndrome that occurs in ~80% of cancer patients and is the primary cause of death for 22%-30% of cancer patients. The primary challenge associated with cancer cachexia is that effective therapies to treat the associated muscle loss and dysfunction are lacking. Research exploring whether reactive oxygen species (ROS, i.e., superoxide anion and hydrogen peroxide) contributes to cancer cachexia has had mixed results. Lipid peroxidation is an underexplored component of oxidative stress that may contribute to cancer cachexia as markers of lipid peroxidation such as 4-hydroxyneoneal (4-HNE) and MDA (Malondialdehyde) are higher in muscle from tumour-bearing mice when compared to controls. Phospholipid hydroperoxide glutathione peroxidase (GPx4) is an antioxidant enzyme that reduces lipid hydroperoxides. We hypothesized that reducing lipid peroxidation via GPx4 overexpression would mitigate cancer cachexia in tumour-bearing mice.
METHODS: One million Lewis lung carcinoma (LLC) cells or phosphate-buffered saline was injected into the hind flank of wildtype or GPx4 transgenic (Tg) mice at 6 months of age and the tumour developed for 4 weeks. Muscle mass, contractile function, mitochondrial respiration, RNA-sequencing, inflammation and the oxylipin profile were assessed.
RESULTS: Muscle mass and myofiber cross-sectional area were reduced ~25% in wildtype tumour-bearing mice compared to control mice but not changed in GPx4 Tg tumour-bearing mice. GPx4 overexpression (~3-fold) did not raise maximal or specific muscle force generation in LLC-tumour-bearing mice. Muscle mitochondrial respiration was reduced in wildtype tumour-bearing mice by ~40% when compared to control mice but not altered in tumour-bearing GPx4 Tg mice. Quadricep RNA seq analysis revealed that expression of inflammatory genes was elevated in wildtype tumour-bearing mice when compared to control mice, and the expression of these genes was reduced in tumour-bearing GPx4 Tg mice compared to wildtype tumour-bearing mice. Next, we found that protein content of IL-6 was ~5-fold greater in muscle from wildtype tumour-bearing mice compared to control mice, and GPx4 overexpression prevented this increase in IL-6. We assessed the muscle oxylipin profile and found that many oxylipins generated by 12/15-Lox were elevated in tumour-bearing mice but not impacted by GPx4 overexpression.
CONCLUSIONS: Our results show that GPx4 overexpression protected muscle mass and mitochondrial respiration in tumour-bearing mice, possibly by reducing muscle inflammation. Future studies will explore the potential mechanisms for the protective effect of GPx4 in cancer cachexia.

Keywords:  GPx4; atrophy; lipid peroxidation; lipoxygenase; oxylipin; skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.70255
J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70246

Deficient Cardiolipin Remodelling Alters Muscle Fibre Composition and Neuromuscular Connectivity in Barth Syndrome.

Catalina Matias, Paige L Snider, Elizabeth A Sierra Potchanant, Joshua R Huot, Rahul Raghav, Michael T Chin, Simon J Conway, Jeffrey J Brault.

   BACKGROUND: Barth syndrome (BTHS) is a rare X-linked mitochondrial disorder caused by mutations in the TAFAZZIN gene, which disrupts cardiolipin (CL) remodelling and mitochondrial function. While cardiac manifestations of BTHS are well characterized in male patients, the mechanisms underlying skeletal muscle weakness and fatigability are poorly understood.
METHODS: We investigated neuromuscular and mitochondrial alterations in a novel murine model (TazPM) carrying a patient-derived D75H point mutation knocked into the Tafazzin locus. This mutation preserves protein abundance but abolishes enzymatic activity. Skeletal muscle function was assessed via weightlifting and hanging tests. Muscle fibre composition and neuromuscular junction (NMJ) integrity were evaluated using immunofluorescence, western blotting and in vivo electrophysiology. Mitochondrial morphology was examined by transmission electron microscopy, and bioenergetics were quantified using ultra-performance liquid chromatography. Stress signalling was assessed by western blotting.
RESULTS: Male TazPM mice exhibited seven-fold elevated total monolysocardiolipin and five-fold reduced mature CL levels, confirming deficient transacylase activity. These mice exhibited lower muscle strength and endurance, 32% smaller muscle fibres of all types and a shift towards fast-twitch type 2B fibres, which are more susceptible to fatigue. Electrophysiological analysis revealed a 60% reduction in motor unit number and an increase in average single motor unit potential, indicating motor neuron remodelling. NMJ protein analysis showed decreased MUSK and DOK7 and increased CHRNA1, suggesting impaired NMJ integrity. Despite mitochondrial structural abnormalities and reduced expression of key mitochondrial proteins (NDUFB8, MCU, TMEM65), resting ATP, phosphocreatine and adenine nucleotide ratios were unchanged in both glycolytic and oxidative muscles. However, stress signalling pathways were markedly activated, including phosphorylation of eIF2α, increased CHOP, DELE1, p53 expression and altered Wnt/β-catenin signalling components.
CONCLUSIONS: Whole-body deficiency of tafazzin enzymatic activity, as occurs in BTHS, is sufficient to result in widespread neuromuscular remodelling, including fibre size/type shifts, motor unit loss, NMJ dysregulation and stress pathway activation, without overt energetic failure at rest. These findings suggest that myopathy in BTHS arises not solely from mitochondrial ATP insufficiency but rather from cumulative structural and signalling adaptations.

Keywords:  ATP; Barth syndrome; adenine nucleotides; cardiolipin; electrophysiology; integrated stress response; mitochondria; neuromuscular junction; skeletal muscle; tafazzin

DOI:  https://doi.org/10.1002/jcsm.70246
J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70253

Impaired Adipose Anabolism in Pancreatic Cancer Cachexia Is Reversed by HuR Inhibition.

Paige C Arneson-Wissink, Katherine Pelz, Beth Worley, Heike Mendez, Peter Pham, Parham Diba, Peter R Levasseur, Grace McCarthy, Alex Chitsazan, Jonathan R Brody, Aaron J Grossberg.

   BACKGROUND: Cachexia is defined by chronic loss of fat and muscle, is a frequent complication of pancreatic ductal adenocarcinoma (PDAC) and negatively impacts patient outcomes. Nutritional supplementation cannot fully reverse tissue wasting, and the mechanisms underlying this phenotype are unclear. This work aims to define the relative contributions of catabolism and anabolism to adipose wasting in PDAC-bearing mice. Human antigen R (HuR) is an RNA-binding protein recently shown to suppress adipogenesis. We hypothesize that fat wasting results from a loss of adipose anabolism driven by increased HuR activity in adipocytes of PDAC-bearing mice.
METHODS: Adult C57BL/6J mice received orthotopic PDAC cell (KrasG12D; p53R172H/+; Pdx1-cre) (PDAC) or PBS (sham) injections. Mice exhibiting moderate cachexia (9 days after injection) were fasted for 24 h, or fasted 24 h and refed 24 h before euthanasia. A separate cohort of PDAC mice were treated with an established HuR inhibitor (KH-3, 100 mg/kg) and subjected to the fast/refeed paradigm. We analysed body mass, gross fat pad mass and adipose tissue mRNA expression. We quantified lipolytic rate as the normalized quantity of glycerol released from 3T3-L1 adipocytes in vitro and gonadal fat pads (gWAT) ex vivo.
RESULTS: 3T3-L1 adipocytes treated with PDAC cell conditioned media (CM) had lower expression of lipolysis and lipogenesis genes than control cells and did not display elevated lipolysis as measured by liberated glycerol. PDAC gWAT cultured ex vivo displayed decreased lipolysis compared to sham gWAT (-54.7%). PDAC and sham mice lost equivalent fat mass after a 24 h fast; however, PDAC mice could not restore inguinal fat pads (iWAT) (-40.5%) or gWAT (-31.8%) mass after refeeding. RNAseq revealed 572 differentially expressed genes in gWAT from PDAC compared to sham mice. Downregulated genes (n = 126) were associated with adipogenesis (adj p = 0.05), and expression of adipogenesis master regulators Pparg and Cebpa were reduced in gWAT from PDAC mice. Immunohistochemistry revealed increased HuR staining in gWAT (+74.9%) and iWAT (+41.2%) from PDAC mice. Inhibiting HuR binding restored lipogenesis in refed animals with a concomitant increase in iWAT mass (+131.7%).
CONCLUSIONS: Our work highlights deficient adipose anabolism as a driver of reduced lipid content in 3T3-L1 adipocytes treated with PDAC conditioned media and PDAC mice. The small molecule KH-3, which disrupts HuR binding, restored adipose anabolism in PDAC mice. This highlights HuR as a potentially targetable regulatory node for adipose anabolism in cancer cachexia.

Keywords:  HuR; adipogenesis; adipose; cachexia; pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.1002/jcsm.70253
Free Radic Biol Med. 2026 Mar 12. pii: S0891-5849(26)00228-5. [Epub ahead of print]249 469-488

Aldh3a1-mediated detoxification of reactive aldehydes contributes to distinct muscle responses to amyotrophic lateral sclerosis progression.

Ang Li, Li Dong, Xuejun Li, Jianxun Yi, Jo-Yu Wu, Jianjie Ma, Jingsong Zhou.

  Different muscles exhibit varied susceptibility to degeneration in Amyotrophic Lateral Sclerosis (ALS), a fatal neuromuscular disorder. Extraocular muscles (EOMs) are particularly resistant to ALS progression, and exploring the underlying molecular nature may offer significant therapeutic value. Reactive aldehyde 4-hydroxynonenal (HNE) is implicated in ALS pathogenesis, and Aldh3a1 is an inactivation-resistant intracellular aldehyde dehydrogenase that detoxifies 4-HNE to protect eyes against UV-induced oxidative stress. We detected prominently higher levels of Aldh3a1 in mouse EOMs compared to other muscles under normal physiological conditions. In an ALS mouse model (hSOD1G93A) reaching end-stage, Aldh3a1 expression was maintained high in EOMs, substantially elevated in soleus and diaphragm, but only moderately increased in extensor digitorum longus (EDL) muscle, which endured the most severe pathological remodeling, as demonstrated by unparalleled upregulation of a denervation marker Ankrd1. Importantly, sciatic nerve transection in wildtype mice further confirmed induced Aldh3a1 and Ankrd1 expression in an inverse manner across muscle types in response to denervation. Mechanistically, whole-muscle RNA-Seq and pharmacological tests indicate that higher basal levels of lipid oxidation and 4-HNE in soleus and diaphragm muscles may render them more susceptible to the induction of certain Nrf2-dependent antioxidant enzymes, including Aldh3a1, under pathological stress relative to the EDL muscle. Additionally, the identification of the myoblast fusion marker Mymk as an EOM signature gene suggests that the spontaneous activation of satellite cells contributes to high levels of Aldh3a1 in EOMs. Functionally, adeno-associated virus-mediated overexpression of Aldh3a1 protected myotubes from 4-HNE-induced DNA fragmentation and plasma membrane leakage. It also restored MG53-mediated membrane repair, highlighting its potential for clinical applications.

Keywords:  Aldehyde dehydrogenase; Amyotrophic lateral sclerosis; Extraocular muscle; Reactive aldehydes; Sciatic nerve transection; Skeletal muscle

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.037
J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70249

Inhibition of N-Terminal Acetyltransferase C Mitigates Endoplasmic Reticulum Stress-Mediated Muscle Atrophy in Cancer Cachexia.

Yusaku Kaneko, Tomohiro Hino, Shunta Taminishi, Yayoi Matoba, Daisuke Motooka, Atsushi Hoshino, Satoaki Matoba.

   BACKGROUND: Cancer cachexia is a complex syndrome marked by weight loss and muscle wasting, significantly impacting patient quality of life and survival. Mechanistically, it is characterized by suppressed protein synthesis and enhanced muscle catabolism, with the role of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) becoming increasingly evident. This study aimed to explore ER stress-tolerant factors in muscle wasting and evaluate their potential to prevent muscle loss in cancer cachexia.
METHODS: A genome-wide CRISPR screening was conducted in the context of ER stress-mediated growth inhibition of C2C12 myoblasts. The candidate genes resistant to ER stress were further evaluated in C2C12 myotubes treated with conditioned medium of Lewis lung adenocarcinoma (LLC) cells. Twelve-week-old male mice were administered LLC cells and shRNA against Naa35 via adeno-associated virus. Four weeks later, tibialis anterior (TA) muscles were analysed for muscle mass, grip strength and molecular changes with quantitative polymerase chain reaction, western blotting and histological analysis.
RESULTS: CRISPR screening identified Naa35, Naa38 and Naa30, all three components of N-terminal acetyltransferase C, as key molecules for resistance to ER stress. The atrophic muscles of mice bearing LLC demonstrated an elevation of UPR, as well as 1.64-fold upregulation of Naa35 protein (p = 0.0072). Among the three branches of the UPR, an ATF6 inhibitor, AEBSF, abolished upregulation of Naa35, Naa38 and Naa30, and an ATF6 activator, AA147, induced Naa35 expression in a dose-dependent manner (p < 0.001). In cells treated with LLC conditioned medium, Naa35 knockdown reduced the amount of cathepsin K (CTSK) protein, which subsequently resulted in the CTSK-mediated proteolysis of insulin receptor substrate 1. In LLC-bearing mice, Naa35 knockdown led to a 65.4% reduction in CTSK protein expression (p < 0.001) and preservation of the phosphorylation levels of protein kinase B (p < 0.0324) and anabolic-related S6 kinase (p < 0.0375). Concurrently, the expression of catabolism-related genes was repressed (MuRF1, p < 0.0015; MAFbx1, p < 0.0265). These alterations were associated with the restoration of TA muscle mass (2.52 ± 0.19 vs. 3.72 ± 0.45 mg/g, p = 0.0004), fibre area (1741 ± 992 vs. 2099 ± 1264 mm2, p < 0.0001), grip strength in all four limbs (0.0328 ± 0.0076 vs. 0.0506 ± 0.0130 N/g, p = 0.0295) and wire mesh hanging time (496 ± 331 vs. 1038 ± 370 s, p = 0.0406).
CONCLUSIONS: Inhibition of N-terminal acetyltransferase C prevents ER stress-induced muscle wasting via the downregulation of CTSK and subsequent activation of the anabolic pathway. This suggests that N-terminal acetyltransferase C is a potential therapeutic target for combating muscle wasting in cancer cachexia.

Keywords:  ER stress; N‐terminal acetyltransferase C; cachexia; muscle atrophy

DOI:  https://doi.org/10.1002/jcsm.70249
Oncol Lett. 2026 May;31(5): 160

Tumor-muscle communication in cancer-associated cachexia (Review).

Lily Berríos-Contreras, Matías Meza-Valenzuela, Nelson Brown, Claudio Valenzuela, Silvia Busquets, Francisco Javier López-Soriano, Andrew Fg Quest, Rodrigo Moore-Carrasco.

  Cancer progression is characterized by the ability of cancer cells to grow uncontrollably, invade adjacent tissues and eventually metastasize, which is typically accompanied by systemic effects. Cachexia, a catabolic state characterized by the loss of skeletal muscle mass and anorexia, is thought to result from the release of inflammatory molecules and other mediators from the tumor niche. The loss of skeletal muscle mass that characterizes cachexia is due to an exacerbation of proteolysis in muscle cells, a catabolic process that is dependent on inflammatory factors and extracellular vesicles (EVs) released by tumor cells. EVs activate various cellular signaling pathways that result in the nuclear translocation of NF-κB. These EVs carry various cargoes, including interleukins, microRNAs and receptors for advanced glycation end-products. When reaching muscle cells, these factors lead to an energy imbalance, increased oxidative stress, and the transcription of ubiquitin ligases such as muscle RING finger 1 and muscle atrophy F-box (Atrogin-1). While EVs appear to play an important role in cachexia, more evidence is needed to determine the interaction of the different cellular signaling pathways involved in the communication between the tumor cells and skeletal muscle cells, as well as to characterize the EVs derived from tumor cells and understand how they may contribute to the varying severity levels of cachexia syndrome. In cachexia, muscle wasting is driven by pro-inflammatory and catabolic factors released by tumor cells, leading to a negative energy balance. These factors activate the ubiquitin-proteasome pathway and suppress the PI3K/AKT/mTOR pathway. This line of research may lead to the development of new therapeutic strategies aimed at improving survival in patients with cancer with cachexia.

Keywords:  cachexia; cancer; catabolism; extracellular vesicles; muscle wasting

DOI:  https://doi.org/10.3892/ol.2026.15513
Matrix Biol. 2026 Mar 17. pii: S0945-053X(26)00024-7. [Epub ahead of print]

Laminin-α2 is required for the maintenance of the myotendinous junction in vivo.

Julia Schedel, Shuo Lin, Thomas Bock, Dominik Burri, Markus A Rüegg.

  The myotendinous junction (MTJ) is a critical interface between muscle fibers and tendons, essential for force transmission between muscle and bone. Laminin-α2, a key extracellular matrix (ECM) component, is strongly enriched at this interface. Mutations in the LAMA2 gene cause LAMA2-related muscular dystrophy (LAMA2 MD), an early-onset severe congenital muscular dystrophy. Here, we examined the MTJ in dyW/dyW mice, a mouse model for LAMA2 MD. We find a strong disruption of MTJ morphology, including altered muscle fiber tips, collagen XXII mislocalization, and reduced muscle tendon interface. As MTJ loading is altered in dyW/dyW mice and MTJ maintenance requires loading and unloading, we also examined MTJ structures upon denervation-induced unloading. While muscle fiber tip morphology resembled that of dyW/dyW mice, collagen XXII distribution was not affected and the muscle-tendon interface was preserved. Finally, proteomic profiling via laser capture microdissection and mass spectrometry revealed significant regional and global shifts in MTJ protein composition in dyW/dyW and denervated mice. Across both models, we identified integrin-associated remodeling as a shared response linked to the perturbed muscle fiber tip morphology. These findings demonstrate that laminin-α2 is required for MTJ stability, and that mechanical unloading contributes to the observed phenotype. Importantly, our results suggest that disruptions in MTJ structure and protein composition may contribute to the pathology observed in LAMA2 MD.

Keywords:  ECM; LAMA2 MD; MTJ; collagen XXII; denervation; dy(W)/dy(W) mice; extracellular matrix; laminin-α2; myotendinous junction

DOI:  https://doi.org/10.1016/j.matbio.2026.03.003
Cancer Res Commun. 2026 Mar 17.

Characterization of mitochondrial double-stranded RNA levels in Non-Small Cell Lung Carcinoma.

Matthew R Krieger, Sandy Che-Eun S Lee, Ting Fu, Maya Cielo Cornejo, Kevin L He, Ryan Howe, Vanessa Saldivar, Angela L Zhang, Guillaume F Chanfreau, Michael A Teitell, Xinshu Xiao, David B Shackelford, Carla M Koehler.

Mitochondrial double-stranded RNA (mtdsRNA) is exported to the cytoplasm when mitochondrial RNA degradation is impaired, serving as a novel damage-associated molecular pattern (DAMP) for mitochondrial stress. Whereas mtdsRNA has been detected in certain cancers, its prevalence and functional role remain largely underexplored. Moreover, mtdsRNA is not readily detectable in large-scale computational datasets, reflecting technical limitations in the detection of structured mitochondrial transcripts. Here, we used comprehensive computational characterization of non-small cell lung cancer (NSCLC) cell lines and identified elevated light-strand transcripts in a subset of cell lines, suggesting a potential for mtdsRNA formation. We stratify NSCLC lines into groups with high and low mtdsRNA abundance. Despite high cytoplasmic mtdsRNA levels in select NSCLC cell lines, we did not identify significant correlation with mtdsRNA abundance and Type-I interferon (IFN-l) response. RT-qPCR analysis revealed that only USP18 transcripts amongst the IFN-l transcripts probed were significantly regulated in select NSCLC lines, indicating a partial or suppressed IFN-I response. Strand-specific RT-qPCR also revealed no bias in mitochondrial gene expression. These findings indicate that basal mtdsRNA accumulation alone is insufficient to trigger IFN-I signaling and may be tolerated in NSCLC, indicating adaptive mechanisms. Our findings suggest that mtdsRNAs could serve alternative non-immunogenic roles in tumor biology. Importantly, our work reports that mtdsRNA is upregulated in a subset of NSCLC cell lines and in other cancer cell types, suggesting that mtdsRNA may serve as a new marker of mitochondrial dysfunction in cancer.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0656
bioRxiv. 2026 Mar 11. pii: 2026.03.02.704798. [Epub ahead of print]

Blood Biochemical Responses to Acute Exercise: Findings from the Molecular Transducers of Physical Activity Consortium (MoTrPAC).

MoTrPAC Study Group

  Exercise benefits numerous organ systems and tissues, however limited knowledge exists about its underlying molecular pathways. Identifying the exercise-induced biochemical changes that occur in the circulation may provide further insights into how exercise confers systemic health changes. Here, we perform large-scale plasma proteomic, metabolomic, and whole blood transcriptional profiling in sedentary human participants undergoing acute endurance exercise (EE), resistance exercise (RE), or a non-exercise control (CON) in up to 7 timepoints over a 24 hour period. We observe 7066 transcript, 189 protein, and 448 metabolite changes in response to EE or RE compared to CON. Our analyses reveal numerous shared biochemical responses between EE and RE modes, but also differences in immune cell responses, lipid metabolism, and pathways reflective of tissue repair and angiogenesis. Taken together, our findings highlight novel temporal and exercise mode-specific blood-based molecular responses to acute exercise, and provide a new resource for the scientific community.

Keywords:  acute exercise response; adipose tissue; biomarkers; cross-tissue analysis; endurance exercise; exercise physiology; exerkines; metabolomics; molecular mechanisms; multi-omics; physical activity; precision medicine; proteomics; resistance exercise; skeletal muscle; systems biology; transcriptomics

DOI:  https://doi.org/10.64898/2026.03.02.704798
Nat Metab. 2026 Mar 18.

Lysosomal phosphoinositide turnover acts upstream of RagGTPase-mTORC1 and controls muscle growth.

Melanie Picot, Nesrine Hifdi, Mathilde Vaucourt, Melanie Mansat, Peng Li, Isabel Singer, Gaëtan Chicanne, Alexandre Stella, Shen Kuang, Caterina Miceli, Nathaniel F Henneman, Bernard Payrastre, Marie Vandromme, Odile Schiltz, Ivan Nemazanyy, Mariana E G de Araujo, Ganna Panasyuk, Julien Viaud, Michael Lämmerhofer, Karim Hnia.

Lysosomes act as metabolic signalling hubs that integrate nutrient availability to coordinate anabolic and catabolic programmes. Mechanistic target of rapamycin complex 1 (mTORC1) is activated at the lysosomal surface by amino acids through RagGTPases recruited by the lysosomal adaptor and MAPK and mTOR activator complex, yet the contribution of lysosomal lipid composition to this pathway remains unclear. Here we identify lysosomal phosphoinositides, PI3P and PI(3,5)P2, as key regulators of lysosomal adaptor and MAPK and mTOR activator complex stability and dynamics at the lysosome. These lipid pools are controlled by the phosphoinositide 3-phosphatase MTM1, mutated in myotubular myopathy, via endoplasmic reticulum-lysosome membrane contact sites. Under endoplasmic reticulum stress, MTM1-dependent phosphoinositide remodelling suppresses RagGTPase-mTORC1 signalling, thereby regulating anabolic-catabolic balance during myogenic differentiation. Restoring mTORC1 activity or lysosomal phosphoinositide homeostasis rescues Rag-dependent signalling and muscle growth in cellular and mouse models of myopathy, uncovering a lysosome-centred metabolic checkpoint with direct disease relevance.

DOI: https://doi.org/10.1038/s42255-026-01484-1