bims-musmir Biomed News
on microRNAs in muscle
Issue of 2025–08–03
eleven papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway
  1. The CCL2-CCR2 axis drives neuromuscular denervation in amyotrophic lateral sclerosis.
  2. Opantimirs: A class of antagonizing microRNAs that upregulate Opa1 and improve mitochondrial and disuse myopathies.
  3. Absence of Parkin Results in Atrophy of Oxidative Myofibers and Modulation of AKT and MURF1 Signaling in Middle-Aged Male Mice.
  4. Loss of Ufsp1 does not cause major changes at the neuromuscular junction.
  5. Hyperactivation of TAK1 causes skeletal muscle pathology reminiscent of inflammatory myopathies.
  6. Metabolic adaptation and fragility in healthy 3-D in vitro skeletal muscle tissues exposed to Chronic Fatigue Syndrome and Long COVID-19 sera.
  7. Morpholino-Mediated Exon Inclusion for Spinal Muscular Atrophy (SMA).
  8. Circulating miR-144-3p as a Novel Independent Biomarker Associated With Low Muscle Strength Among Older Adults.
  9. Synergic action of MicroRNAs and Wnts delivered by motor neuron EVs in promoting AChR clustering.
  10. Mitochondrial complex I deficiency induces Alzheimer's disease-like signatures that are reversible by targeted therapy.
  11. Aberrant lysosomal dynamics disrupt myogenesis via mTORC1 signalling in X-linked myotubular myopathy.
  1. Nat Commun. 2025 Aug 01. 16(1): 7053
    The CCL2-CCR2 axis drives neuromuscular denervation in amyotrophic lateral sclerosis.
    Bernát Nógrádi, Kinga Molnár, Rebeka Kristóf, Orsolya Horváth, Yu-Ting Huang, Zara Ridgway, Amaia Elicegui, Sandra Fuertes-Alvarez, Sonia Alonso-Martin, Gábor J Szebeni, Nikolett Gémes, Abdullah Ramadan, Hannah L Smith, István A Krizbai, Roland Patai, László Siklós, Péter Klivényi, Helena Chaytow, Thomas H Gillingwater.
      Systemic immune changes have been implicated in amyotrophic lateral sclerosis (ALS), but precise mechanisms and cellular targets remain unknown. Neuromuscular junction (NMJ) denervation is another major pathophysiological event in ALS, but it remains unclear whether immune system dysregulation contributes to this process. Here, we report leukocyte and macrophage infiltration in ALS patient-derived skeletal muscle biopsies. Immune cell infiltration was replicated across the hTDP-43, TDP-43A315T (male only) and TDP-43M337V mouse models, occurring from pre-symptomatic stages and targeted to NMJ-enriched muscle regions. Proteomic analysis implicated the CCL2-CCR2 axis as a driving factor. CCL2+ cells were enriched around NMJs in hTDP-43 mice, and in ALS patient skeletal muscle. Local treatment with CCL2-neutralising antibodies or normal IgG antibodies in hTDP-43 mice reduced leukocyte infiltration and ameliorated NMJ denervation. These results demonstrate that the CCL2-CCR2 axis drives immune cell infiltration targeting NMJs in ALS, identifying a potential avenue for therapeutic intervention to prevent NMJ denervation.
    DOI:  https://doi.org/10.1038/s41467-025-62351-3
  2. Cell Rep Med. 2025 Jul 16. pii: S2666-3791(25)00321-0. [Epub ahead of print] 102248
    Opantimirs: A class of antagonizing microRNAs that upregulate Opa1 and improve mitochondrial and disuse myopathies.
    Andre Djalalvandi, Keisuke Takeda, Francesca Grespi, Hualin Fan, Tiago Branco Fonseca, Leonardo Nogara, Saman Sharifi, Carlotta Barison, Martina Semenzato, Akiko Omori, Raffaele Cerutti, Davide Steffan, Lorenza Tsansizi, Valeria Balmaceda, Lukas Alan, Camilla Bean, Bert Blaauw, Carlo Viscomi, Luca Scorrano.
      Alterations in mitochondrial ultrastructure and reduced levels of the crista-shaping protein Opa1 are key features of mitochondrial myopathies and aging. We identify and characterize a biological therapy that improves mitochondrial and disuse myopathy models by boosting Opa1 levels. In silico analysis identifies microRNAs (miRNAs) 128-3p and 148/152-3p family as conserved modulators of OPA1 transcription and elevated in various muscle disorders. These miRNAs target the 3' UTR of murine and human OPA1, reducing its mRNA and protein levels, causing mitochondrial fragmentation and crista disorganization. Genetic experiments confirm that their mitochondrial effects rely on 3' UTR binding. In mitochondrial disease patient cells and murine models, elevated OPA1-specific miRNA levels are reduced by antagonistic miRNAs (Opantimirs), which restore mitochondrial ultrastructure, morphology, and function. In vivo, Opantimirs correct mitochondrial ultrastructure and fiber size in muscles of denervated and Cox15-ablated mice, improving strength in the latter. Thus, biopharmacological correction of the mitochondrial ultrastructure can ameliorate mitochondrial myopathies.
    Keywords:  OPA1; antimiRs; cristae remodeling; disuse myopathies; miR-128-3p; miR-148/152-3p family; microRNAs; mitochondrial myopathies; mitochondrial ultrastructure
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102248
  3. Acta Physiol (Oxf). 2025 Sep;241(9): e70082
    Absence of Parkin Results in Atrophy of Oxidative Myofibers and Modulation of AKT and MURF1 Signaling in Middle-Aged Male Mice.
    Isabela Aparecida Divino, Ana Laura da Vieira-da-Silva, Marcos Vinicius Esteca, Rafael Paschini Tonon, Felipe Oliveira Gomes da Cruz, Renata Rosseto Braga, Eduardo Rochete Ropelle, Paulo Guimarães Gandra, Igor Luchini Baptista.
       AIM: This work aimed to investigate the effects of the loss of Parkin in middle-aged mice skeletal muscle, focusing on different types of myofibers and in the analysis of proteins related to protein synthesis and degradation as well as the analysis of force generation and motor balance.
    METHODS: We used male mice C57BL/6J (WT) and Parkin knockout mice, Parkintm1Shn (Parkin-/-) at 3 and 10 months of age. We used Walking Beam, Open Field, Spider Mice and Maximum Power Tests to assess motor, balance, and endurance functions. We used flexor digitorum brevis (FDB) muscle for force generation analysis, and tibial anterior (TA) and soleus (SOL) muscles were used for biomolecular techniques because of their difference in fiber type. These muscles were used to investigate markers of protein synthesis and degradation, mitochondrial respiration, and myofiber diameter.
    RESULTS: The Absence of Parkin in middle-aged mice leads to a reduction in isometric force generation but maintained overall motor and locomotion abilities, exhibited only minor balance deficits. In the SOL muscle of middle-aged Parkin-/- mice, we observed a reduction of muscle mass and myofiber diameter, also a significant decrease in mitochondrial respiratory capacity and Complex V. In the same group, we observed a reduction in the phosphorylation of AKT and 4E-BP1, and an increase in MURF-1 while Ubiquitin K63 levels decreased. We did not observe relevant differences in the TA muscle.
    CONCLUSION: Our results suggest middle-aged Parkin-/- mice exhibited muscle atrophy and mitochondrial dysfunction primarily in oxidative myofibers before noticeable motor dysfunction occurs.
    Keywords:  E3 ubiquitin ligase; aging; muscle loss; protein synthesis signaling; skeletal muscle
    DOI:  https://doi.org/10.1111/apha.70082
  4. PLoS One. 2025 ;20(8): e0328690
    Loss of Ufsp1 does not cause major changes at the neuromuscular junction.
    Cristofer Calvo, Coalesco Smith, Taejeong Song, Fabian Montecino-Morales, Sakthivel Sadayappan, Douglas P Millay, Minchul Kim.
      UFMylation is a Ubiquitin-like post-translational modification involved in myriad of cellular processes. Enzymes involved in this pathway, including ligases and UFM1-specific proteases, are essential for development and homeostasis. Our previous transcriptomic analyses identified an enrichment of Ufsp1 at the neuromuscular junction of skeletal muscle cells. Ufsp1, one of the two UFM1 proteases, had been considered a pseudogene due to truncation of its catalytic domain in several species, including humans. However, recent findings revealed that Ufsp1 is translated from a non-canonical start codon in humans, yielding a catalytically active enzyme. This discovery has revived interest in studying Ufsp1's role in vivo. We generated two mutant mouse models, one with a point mutation abolishing catalytic activity and another with complete knockout of the gene. Unlike other UFMylation pathway enzymes, both Ufsp1 mutants were born in normal ratios and did not exhibit gross phenotypic abnormalities. Despite the enrichment of Ufsp1 at neuromuscular junctions, only mild structural alterations of this synapse were detected, which did not impact overall muscle function. Our findings indicate that Ufsp1 is dispensable for normal development and homeostasis in mice, but further exploration of its function is needed in pathological conditions.
    DOI:  https://doi.org/10.1371/journal.pone.0328690
  5. Am J Pathol. 2025 Jul 24. pii: S0002-9440(25)00249-4. [Epub ahead of print]
    Hyperactivation of TAK1 causes skeletal muscle pathology reminiscent of inflammatory myopathies.
    Meiricris Tomaz da Silva, Anirban Roy, Ashok Kumar.
      Loss of skeletal muscle mass and strength is a debilitating consequence of various chronic diseases, inflammatory myopathies, and neuromuscular disorders. Inflammation plays a major role in the perpetuation of myopathy in degenerative muscle diseases. TGF-β-activated kinase 1 (TAK1) is a major signaling protein that mediates the activation of multiple signaling pathways in response to inflammatory cytokines and microbial products. Recent studies have demonstrated that TAK1 is essential for the growth and maintenance of skeletal muscle mass in adult mice. However, the effects of overstimulation of TAK1 activity in the regulation of skeletal muscle mass remain unknown. The present study investigated the effects of varying levels of TAK1 activation on skeletal muscle in adult mice. Results showed that while low levels of TAK1 activation improve skeletal muscle mass, sustained hyperactivation of TAK1 causes myopathy in adult mice. Excessive stimulation of TAK1 manifested pathological features, such as myofiber degeneration and regeneration, cellular infiltration, increased expression of proinflammatory molecules, and interstitial fibrosis. Hyperactivation of TAK1 also upregulated proteolytic systems and various catabolic signaling pathways in skeletal muscle of adult mice. Altogether, this study demonstrated that physiological levels of activation of TAK1 lead to myofiber hypertrophy, whereas its hyperactivation results in myofiber damage and other pathological features resembling inflammatory myopathies.
    DOI:  https://doi.org/10.1016/j.ajpath.2025.07.005
  6. Biofabrication. 2025 Jul 31.
    Metabolic adaptation and fragility in healthy 3-D in vitro skeletal muscle tissues exposed to Chronic Fatigue Syndrome and Long COVID-19 sera.
    Sheeza Mughal, Félix Andújar-Sánchez, Maria Sabater-Arcis, Glória Garrabou, Joaquim Fernández-Solà, Jose Alegre-Martin, Ramon Sanmartin Sentañes, Jesus Castro-Marrero, Anna Esteve-Codina, Eloi Casals, Juan M Fernández-Costa, Javier Ramón-Azcón.
      Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID-19 (LC-19) are complex conditions with no diagnostic markers or consensus on disease progression. Despite extensive research, no in vitro model exists to study skeletal muscle wasting, peripheral fatigue, or potential therapies. We developed 3D in vitro skeletal muscle tissues to map muscle adaptations to patient sera over time. Short exposures (48 hours) to patient sera led to a significant reduction in muscle contractile strength. Transcriptomic analysis revealed the upregulation of glycolytic enzymes, disturbances in calcium homeostasis, hypertrophy, and mitochondrial hyperfusion. Structural analyses confirmed myotube hypertrophy and elevated mitochondrial oxygen consumption in ME/CFS. While muscles initially adapted by increasing glycolysis, prolonged exposure (96-144 hours) caused muscle fragility and fatigue, with mitochondria fragmenting into a toroidal conformation. We propose that skeletal muscle tissue in ME/CFS and Long COVID-19 progresses through a hypermetabolic state, leading to severe muscular and mitochondrial deterioration. This is the first study to suggest such transient metabolic adaptation.&#xD.
    Keywords:  Long Covid-19; chronic fatigue syndrome; metabolic adaptation; skeletal muscle
    DOI:  https://doi.org/10.1088/1758-5090/adf66c
  7. Methods Mol Biol. 2025 ;2964 433-444
    Morpholino-Mediated Exon Inclusion for Spinal Muscular Atrophy (SMA).
    Haiyan Zhou, Francesco Muntoni.
      The application of antisense oligonucleotides (AONs) to modify pre-messenger RNA splicing has great potential for treating genetic diseases. The strategies used to redirect splicing for therapeutic purposes involve the use of AONs complementary to splice motifs, enhancer or silencer sequences. AONs to block intronic splicing silencer motifs can efficiently augment exon 7 inclusion in the survival motor neuron 2 (SMN2) gene and have demonstrated robust therapeutic effects in both pre-clinical studies and clinical trials in spinal muscular atrophy (SMA), which has led to the approval of nusinersen. AONs with phosphoroamidate morpholino (PMO) backbone have shown target engagement with restoration of the defective protein in Duchenne muscular dystrophy (DMD) and their safety profile lead to the approval of four DMD AON drugs. PMO AONs are also effective in correcting SMN2 exon 7 splicing and rescuing SMA transgenic mice. Here we provide the details of methods that our lab has used to evaluate PMO-mediated SMN2 exon 7 inclusion in the in vivo studies conducted in SMA transgenic mice. The methods comprise mouse experiment procedures, assessment of PMOs on exon 7 inclusion at RNA levels by reverse transcription PCR and quantitative real-time PCR. In addition, we present methods for protein quantification using western blot in mouse tissues, for neuropathology assessment of skeletal muscle (e.g. muscle pathology and neuromuscular junction staining) as well as behaviour test in the SMA mice (e.g. righting reflex).
    Keywords:  Alternative splicing; Antisense oligonucleotide; Exon inclusion; Motor neurons; Neuromuscular junction; PMO; SMA; SMN2; Skeletal muscle pathology; Transgenic mouse model
    DOI:  https://doi.org/10.1007/978-1-0716-4730-1_28
  8. J Cachexia Sarcopenia Muscle. 2025 Aug;16(4): e70026
    Circulating miR-144-3p as a Novel Independent Biomarker Associated With Low Muscle Strength Among Older Adults.
    Hyung Eun Shin, Chang Won Won, Gustavo Duque, Miji Kim.
       BACKGROUND: Low muscle strength, a key component of sarcopenia, is significant in the development of adverse health outcomes among older adults. MicroRNAs (miRNAs) have been implicated in mechanisms of sarcopenia; however, their specific functions in sarcopenia components, particularly low muscle strength, remain unclear. We aimed to examine distinct miRNA signatures associated with muscle mass, strength, and performance and to explore independent biomarkers for identifying older adults with low muscle strength.
    METHODS: Ninety-six older adults were selected from the Korean Frailty and Aging Cohort Study using stratified random sampling based on age and sex, and classified into four groups according to Asian Working Group for Sarcopenia 2019 criteria: normal (n = 25), low muscle mass (Low MM)-only (n = 23), low muscle strength (Low MS)-only (n = 25) and low physical performance (Low PP)-only (n = 23). MiRNA profiles were generated through miRNA sequencing, and differentially expressed (DE) miRNAs among groups were identified using log2|Fold Change (FC)| ≥ 1 and a Benjamini-Hochberg (BH)-adjusted p < 0.05. Subsequently, candidate miRNAs were validated by quantitative real-time polymerase chain reaction. Differences in relative miRNA expression between groups were assessed using analysis of variance. The utility of identified miRNAs for discriminating older adults with low muscle strength was assessed using receiver operating characteristic (ROC) analysis.
    RESULTS: In 96 older adults (50.0% women, mean age 76.6 ± 3.6 years), 16, 5 and 1 DE miRNAs were observed in comparisons of Low MS-only vs. Low MM-only, Low PP-only vs. Low MM-only, and Low PP-only vs. Low MS-only, respectively (log2|FC| ≥ 1 and BH-adjusted p < 0.05). Among these, miR-144-3p, miR-142-3p and miR-122-3p overlapped across at least two comparisons. In the validation phase, miR-144-3p exhibited significantly higher expression in the Low MS-only group than in other groups. Areas under the ROC curve (AUC) for miR-144-3p were 0.943 (95% CI = 0.854-1.000), 0.836 (95% CI = 0.698-0.974) and 0.844 (95% CI = 0.700-0.989) for distinguishing the Low MS-only group from normal, Low MM-only and Low PP-only groups, respectively (p < 0.001). Kyoto Encyclopedia of Genes and Genomes analysis revealed that identified novel miRNAs were mainly associated with FoxO and insulin signalling (BH-adjusted p < 0.001), with a trend toward neurotrophic signalling (BH-adjusted p = 0.0647).
    CONCLUSIONS: miR-144-3p was identified as a novel biomarker for low muscle strength among older adults, independent of muscle mass and physical performance. Longitudinal studies are required to determine whether the identified miRNAs can function as predictive biomarkers for muscle strength decline.
    Keywords:  components; miRNAs; muscle strength; older adults; profiling; sarcopenia
    DOI:  https://doi.org/10.1002/jcsm.70026
  9. Cell Commun Signal. 2025 Aug 01. 23(1): 360
    Synergic action of MicroRNAs and Wnts delivered by motor neuron EVs in promoting AChR clustering.
    Rachele Agostini, Paola Ceccaroli, Emanuela Polidori, Manuela Ferracin, Ilaria Pace, Serena Maggio, Andrea Cioccoloni, Michela Battistelli, Giulia Matacchione, Matilde Sbriscia, Fabiola Olivieri, Fabrizia Cesca, Vilberto Stocchi, Michele Guescini.
       BACKGROUND: The neuromuscular junction (NMJ) establishment occurs through complex communication events between motor neurons and muscle fibers; however, the molecular mechanisms leading to NMJ formation have yet to be fully elucidated. Little is known about the significance of extracellular vesicles (EVs) in mediating the interaction between motor neurons and muscle fiber in the NMJ establishment; this study investigates the role of motor neuron-derived EVs during the earliest stages of NMJ formation.
    METHODS: NSC-34 cells have been used as a model of motor neurons; EVs have been isolated during neurite development using a serial ultracentrifugation protocol specifically adjusted to isolate large and small EVs. Isolated EVs were quantified through Nanoparticles Tracking Assay and characterized by Western Blot and TEM analyses. The microRNA (miRNA) cargo of EV subpopulations was identified by small-RNA sequencing and the predicted miRNA downstream targets were investigated.
    RESULTS: NGS analysis of small RNAs carried by NSC-34-derived EVs identified a total of 245 EV specific miRNAs, most of which are up-regulated in NSC-34 cells and EVs during neurite stretching. Target prediction analysis evidenced how these miRNAs synergically target the Wnt signaling pathway. Moreover, we found that NSC-34-derived EVs carry Wnt proteins, including Wnt11, Wnt4 and Wnt3a. Since several studies suggested a role for the Wnt-associated signaling network in NMJ formation, we investigated the potential role of NSC-34 EVs in NMJ development and demonstrated that EV administration to myotubes increases acetylcholine receptor (AChR) cluster formation, as revealed by immunofluorescence staining with α-bungarotoxin. Moreover, myotube treatment with NSC-34-derived EVs led to GSK3β and JNK phosphorylation, followed by β-catenin nuclear translocation, suggesting that neuron-derived EVs can induce AChR clustering through Wnt pathway activation.
    CONCLUSION: These data demonstrate that EVs released from differentiated motor neurons carry multimodal signals, miRNAs, and Wnts, which can stimulate AChR clustering in myotubes, a fundamental preparatory stage for NMJ formation. These new data highlight that EVs may play a role in the NMJ establishment and function under physiological and pathological conditions, particularly neurodegenerative diseases.
    Keywords:  Acetylcholine receptor; Agrin; Extracellular vesicles; Neuromuscular junctions; Wnt signalling; β-catenin
    DOI:  https://doi.org/10.1186/s12964-025-02312-x
  10. Alzheimers Dement. 2025 Aug;21(8): e70519
    Mitochondrial complex I deficiency induces Alzheimer's disease-like signatures that are reversible by targeted therapy.
    Huanyao Gao, Kate Jensen, Jarred Nesbitt, Mark Ostroot, Gregory A Cary, Jesse Wiley, Sergey Trushin, Jens O Watzlawik, Wolfdieter Springer, Alexander Galkin, Priyanka Baloni, Cory Funk, Eugenia Trushina.
       INTRODUCTION: Mitochondrial dysfunction is implicated in Alzheimer's disease (AD), but whether it drives AD-associated changes is unclear. We assessed transcriptomic alterations in the brains of Ndufs4-/- mice, a model of mitochondrial complex I (mtCI) deficiency, and evaluated the therapeutic effects of the neuroprotective mtCI inhibitor CP2.
    METHODS: Cortico-hippocampal tissue from Ndufs4-/- and wild-type mice was subjected to transcriptomic analysis, followed by cross-species comparisons to human late-onset AD and familial AD mouse datasets.
    RESULTS: Knockout of Ndufs4-mediated mtCI deficiency disrupted mitochondrial homeostasis, energy metabolism, and synaptic gene expression, recapitulating transcriptomic signatures of AD. CP2 treatment partially reversed these changes, with female Ndufs4-/- mice showing greater compensatory adaptations and treatment responses.
    DISCUSSION: Loss of mtCI activity alone is sufficient to induce AD-like molecular changes in the brain, independent of amyloid beta or phosphorylated tau. CP2-mediated rescue highlights the potential of targeting mitochondria as a therapeutic strategy for AD. Sex-specific responses suggest important considerations for personalized therapeutics.
    HIGHLIGHTS: Activity of mitochondrial complex I (mtCI) affects broad mitochondrial and neuronal transcriptional networks. A reduction of mtCI activity is sufficient to induce transcriptomic changes reminiscent of those observed in late-onset Alsheimer's disease (AD) patients and familial mouse models of AD. Pharmacological targeting of mtCI mediates neuroprotective signaling. Male and female mice have differential responses to the loss of mtCI activity and to the mitochondria-targeted therapeutics. Mitochondria play a key role in AD development and treatment.
    Keywords:  Alzheimer's disease; Ndufs4 knockout mice; biological domains; mitochondrial complex I; mitochondria‐targeted therapeutics; mitophagy; sex‐specific differences; sex‐specific response; transcriptomic analysis; ubiquitin; weak complex I inhibitors
    DOI:  https://doi.org/10.1002/alz.70519
  11. Brain. 2025 Jul 29. pii: awaf278. [Epub ahead of print]
    Aberrant lysosomal dynamics disrupt myogenesis via mTORC1 signalling in X-linked myotubular myopathy.
    Kengo Kora, Takeshi Yoshida, Atsushi Yokoyama, Kei Fujiwara, Naoko Yano, Taisei Kayaki, Satoshi Kajimoto, Kinuko Nishikawa, Hidetoshi Sakurai, Junko Takita.
      X-linked myotubular myopathy is a severe congenital muscle disorder caused by pathogenic variants in the MTM1 gene, which encodes the phosphoinositide phosphatase myotubularin. Muscle biopsies from patients with X-linked myotubular myopathy exhibit distinctive histopathological features, including small, rounded myofibres with centrally located nuclei, indicating a developmental defect in muscle maturation. While earlier studies have indicated that myotubularin dysfunction causes dysregulation of mechanistic target of rapamycin complex 1 (mTORC1) signalling, the underlying mechanisms and phenotypic impact on human muscle cells remain poorly understood. Currently, there are no approved therapies available for the treatment of this disorder. In this study, we established an induced pluripotent stem cell-based model of X-linked myotubular myopathy using two pairs of isogenic induced pluripotent stem cells: healthy-control versus MTM1-knockout and patient-derived versus gene-corrected induced pluripotent stem cells. Through MyoD-inducible myogenic differentiation, this model successfully recapitulates the key pathological features of X-linked myotubular myopathy, including elevated phosphatidylinositol-3-phosphate levels, hyperactivation of mTORC1 signalling, and increased expression of integrin-β1 and dynamin 2. We identified impaired lysosomal dynamics as a novel pathogenic mechanism in X-linked myotubular myopathy. Our induced pluripotent stem cell-derived X-linked myotubular myopathy myotubes exhibited an abnormal redistribution of lysosomes, with peripheral accumulation, leading to abnormally activated mTORC1 signalling. FYCO1 knockdown, a key regulator of lysosomal trafficking, ameliorated this hyperactivation of mTORC1 signalling. Comprehensive transcriptome analysis revealed distinct gene expression patterns associated with altered mTORC1 signalling and lysosomal localisation in X-linked myotubular myopathy myotubes. Network analysis suggested the central role of the mTORC1 signalling pathway and its connections to disrupted muscle development and differentiation. To investigate the influence of mTORC1 signalling and myotubularin deficiency on myogenic differentiation, we established two mouse myoblast models: one with constitutively activated mTORC1 signalling and another with Mtm1 knockout. Increased mTORC1 signalling in mouse myoblasts impaired myogenic differentiation, and this impairment was reversed by mTORC1 inhibitor rapamycin. Notably, rapamycin treatment also ameliorated the impaired myogenic differentiation observed in Mtm1-knockout mouse myoblasts, supporting the causative role of mTORC1 hyperactivation in X-linked myotubular myopathy pathogenesis. In conclusion, our findings establish the first human cell model of XLMTM, revealing that myotubularin deficiency leads to impaired lysosomal dynamics, which in turn causes mTORC1 dysregulation, a critical factor in the early stage of myogenic differentiation in X-linked myotubular myopathy. These findings provide new insights into the pathogenesis of X-linked myotubular myopathy and suggest that targeting mTORC1 signalling may be a promising therapeutic strategy for this debilitating disorder.
    Keywords:  MTM1; X-linked myotubular myopathy; induced pluripotent stem cell; lysosomal dynamics; mTORC1 signalling; myogenic differentiation
    DOI:  https://doi.org/10.1093/brain/awaf278
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