bims-musmir Biomed News
on microRNAs in muscle
Issue of 2025–03–23
eight papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway
  1. Generation of a novel mouse model of nemaline myopathy due to recurrent NEB exon 55 deletion.
  2. Six-hour hypoxia induced protein degradation in M. gastrocnemius of 24-day-old mice by activating FOXO1 and suppressing AKT-mTORC1.
  3. A molecular systems architecture of neuromuscular junction in amyotrophic lateral sclerosis.
  4. Skeletal muscle atrophy induced by aging and disuse atrophy are strongly associated with the upregulation of the endoplasmic stress protein CHOP in rats.
  5. Sex-Specific Markers of Neuroinflammation and Neurodegeneration in the Spinal Cord Proteome of the SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis.
  6. Developmental mitochondrial complex I activity determines lifespan.
  7. miR-27a-5p, miR-21-5p, miR-1246 and miR-4508: a candidate microRNA signature in the protection and regulation of viral infection in mild COVID-19.
  8. Circulating miR-223/NLRP3 axis and IL-1β level in functional disease progression of amyotrophic lateral sclerosis.
  1. Skelet Muscle. 2025 Mar 20. 15(1): 8
    Generation of a novel mouse model of nemaline myopathy due to recurrent NEB exon 55 deletion.
    Zachary Coulson, Justin Kolb, Nesrin Sabha, Esmat Karimi, Zaynab Hourani, Coen Ottenheijm, Henk Granzier, James J Dowling.
      Biallelic pathogenic variants in the nebulin (NEB) gene lead to the congenital muscle disease nemaline myopathy. In-frame deletion of exon 55 (ΔExon55) is the most common disease-causing variant in NEB. Previously, a mouse model of NebΔExon55 was developed; however, it presented an uncharacteristically severe phenotype with a near complete reduction in Neb transcript expression that is not observed in NEB exon 55 patients. We identified by RNA sequencing that the cause of this unexpectedly severe presentation in mice is the generation of a pseudoexon containing two premature termination codons (and promoting nonsense mediated decay) at the Neb exon 55 deletion site. To prove that this is the cause of the loss of Neb transcript, and to generate a more faithful model of the human disease, we used CRISPR gene editing to remove the pseudoexon sequence and replace it with human intron 54 sequence containing a validated cas9 gRNA protospacer. The resulting "hmz" mice have a significant reduction in pseudoexon formation (93.6% reduction), and a re-introduction of stable Neb transcript expression. This new model has the characteristic features of nemaline myopathy at the physiological, histological, and molecular levels. Importantly, unlike the existing exon 55 deletion mice (which die by age 7 days), it survives beyond the first months and exhibits obvious signs of neuromuscular dysfunction. It thus provides a new, robust model for studying pathomechanisms and developing therapies for NEB related nemaline myopathy.
    Keywords:  CRISPR; Nebulin; Nemaline myopathy; Phenotyping; Pseudoexon; Transcript stabilization
    DOI:  https://doi.org/10.1186/s13395-025-00378-2
  2. Am J Physiol Endocrinol Metab. 2025 Mar 17.
    Six-hour hypoxia induced protein degradation in M. gastrocnemius of 24-day-old mice by activating FOXO1 and suppressing AKT-mTORC1.
    Jingyi Song, Marcel Jaklofsky, Claudia Carmone, Vincent de Boer, Niels Wever, Jaap Keijer, Sander Grefte.
      Long-term hypoxia has been associated with skeletal muscle atrophy, including increased protein degradation over protein synthesis. This contrasts sharply with muscle hypertrophy and net protein synthesis occurring in developing skeletal muscle of young mice. Here, we aimed to understand the impact of acute, physiologically plausible environmental hypoxia on muscle proteostasis of the M. gastrocnemius of young mice. Fasted prepubertal, 24-day-old male B6JRccHsd(B6J)-Nnt+/Wuhap mice with similar body weight and lean mass were exposed to normobaric hypoxia (12% O2) or normoxia (20.9% O2) for 6 hours. The transcriptome (n=12) and protein (n=6) response of the M. gastrocnemius were analyzed. A hypoxic response of M. gastrocnemius was confirmed by increased expression of HIF1 (Ankrd37 and Ddit4) and forkhead box-O (FOXO) 1 (Depp1 and Ddit4) target genes. RNA-Seq analysis revealed that hypoxia activated FOXO signaling, which was confirmed by increased FOXO1 protein levels and decreased p-AKT/AKT ratio. Detailed mapping of the FOXO1 pathway suggests a strong FOXO1-mediated hypoxic effect on protein degradation and synthesis. A central role of Atf4 is suggested by the hypoxic-dependent positive correlations with FOXO1, FBXO32, Depp1, Eif4ebp1 and Ddit4. Further analyses showed increased FBXO32, which positively correlated with FOXO1, and decreased p-S6K/S6K and p-4E-BP1/4E-BP1 ratios. Our results showed for the first time that a 6-hour exposure to 12% O2 normobaric hypoxia in 24-day-old mice activates FOXO1 signaling in M. gastrocnemius, resulting in decreased protein synthesis and increased protein degradation most likely via reduced energy availability, which may be relevant for infant air or high altitude traveling.
    Keywords:  FOXO1; Hypoxia; Proteostasis; Skeletal muscle; mTORC1
    DOI:  https://doi.org/10.1152/ajpendo.00508.2024
  3. NPJ Syst Biol Appl. 2025 Mar 17. 11(1): 27
    A molecular systems architecture of neuromuscular junction in amyotrophic lateral sclerosis.
    V A Shiva Ayyadurai, Prabhakar Deonikar, Roger D Kamm.
      A molecular systems architecture is presented for the neuromuscular junction (NMJ) in order to provide a framework for organizing complexity of biomolecular interactions in amyotrophic lateral sclerosis (ALS) using a systematic literature review process. ALS is a fatal motor neuron disease characterized by progressive degeneration of the upper and lower motor neurons that supply voluntary muscles. The neuromuscular junction contains cells such as upper and lower motor neurons, skeletal muscle cells, astrocytes, microglia, Schwann cells, and endothelial cells, which are implicated in pathogenesis of ALS. This molecular systems architecture provides a multi-layered understanding of the intra- and inter-cellular interactions in the ALS neuromuscular junction microenvironment, and may be utilized for target identification, discovery of single and combination therapeutics, and clinical strategies to treat ALS.
    DOI:  https://doi.org/10.1038/s41540-025-00501-5
  4. Mol Biol Rep. 2025 Mar 18. 52(1): 322
    Skeletal muscle atrophy induced by aging and disuse atrophy are strongly associated with the upregulation of the endoplasmic stress protein CHOP in rats.
    J Max Michel, Joshua S Godwin, Nathan R Kerr, Thomas E Childs, Frank W Booth, C Brooks Mobley, David C Hughes, Michael D Roberts.
       BACKGROUND: While canonical anabolic and proteolytic pathways have been well examined in the context of skeletal muscle proteostasis, the roles of endoplasmic reticulum stress (ERS) and the induced unfolded protein response (UPR) are underappreciated. Thus, we aimed to determine whether aging and/or disuse atrophy in rats altered skeletal muscle ERS/UPR markers.
    METHODS AND RESULTS: Soleus (SOL) and plantaris (PLT) muscles of 3-month-old (mo), 6 mo, 12 mo, 18 mo, and 24 mo rats (9-10 per group, 48 in total) were analyzed for UPR proteins with further analysis performed on the protein CHOP. The gastrocnemius muscles of 4 mo rats that had undergone hindlimb immobilization (HLI, n = 12) or sham casting (CTL, n = 12) were analyzed for similar targets as well as more extensive CHOP-related targets. CHOP protein was greater in the PLT and SOL of 18 and 24 mo rats versus other age groups (P < 0.05). Moreover, negative correlations existed between CHOP expression and normalized PLT (R=-0.702, P < 0.001) and SOL (R=-0.658, P < 0.001) muscle weights in all rats analyzed at different ages. CHOP protein expression was also greater in the gastrocnemius of HLI versus CTL rats (P < 0.001), and a negative correlation existed between CHOP protein expression and normalized muscle weights in these rats (R=-0.814, P < 0.001). Nuclear CHOP protein levels (P < 0.010) and genes transcriptionally regulated by CHOP were also greater in HLI versus CTL rats (P < 0.001) implicating transcriptional activity of CHOP is elevated during disuse atrophy.
    CONCLUSIONS: CHOP is operative during aging- and disuse-induced skeletal muscle atrophy in rodents, and more research is needed to determine if CHOP is a key mechanistic driver of these processes.
    Keywords:  Aging; CHOP; Disuse; Endoplasmic reticulum stress; Unfolded protein response
    DOI:  https://doi.org/10.1007/s11033-025-10415-4
  5. J Proteome Res. 2025 Mar 21.
    Sex-Specific Markers of Neuroinflammation and Neurodegeneration in the Spinal Cord Proteome of the SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis.
    Liam M Koehn, Joel R Steele, Ralf B Schittenhelm, Joseph A Nicolazzo.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that has no cure. The underlying mechanistic details of sex differences in the ALS spinal cord, the site of disease onset, are not understood to an extent that could guide novel drug development. To address this, the spinal cords of 120-day-old wild-type (WT) and SOD1G93A (familial mouse model of ALS with mutant superoxide dismutase 1) mice were subjected to untargeted, quantitative proteomics using tandem mass tag acquisition on high-resolution mass spectrometric instrumentation. Compared to WT, both male and female SOD1G93A spinal cords exhibited an upregulation of neuroinflammatory cascades of both peripheral and central origins, as well as a downregulation of proteins reflective of death and dysfunction of cells within the spinal cord. However, female and male SOD1G93A mouse spinal cords exhibited sex-specific differences in proteins compared to respective WT that related to immune response, as well as cellular structure, function, and homeostasis. The proteomic datasets presented provide entire cohort and sex-specific spinal cord drug targets and disease biomarkers in the SOD1G93A mouse model of ALS that may guide future drug development and sex selection in preclinical study designs utilizing the SOD1G93A model.
    Keywords:  SOD1G93A; amyotrophic lateral sclerosis; inflammation; motor neurone disease; neurodegeneration; proteomics; sex; spinal cord
    DOI:  https://doi.org/10.1021/acs.jproteome.4c00990
  6. EMBO Rep. 2025 Mar 17.
    Developmental mitochondrial complex I activity determines lifespan.
    Rhoda Stefanatos, Fiona Robertson, Beatriz Castejon-Vega, Yizhou Yu, Alejandro Huerta Uribe, Kevin Myers, Tetsushi Kataura, Viktor I Korolchuk, Oliver D K Maddocks, L Miguel Martins, Alberto Sanz.
      Aberrant mitochondrial function has been associated with an increasingly large number of human disease states. Observations from in vivo models where mitochondrial function is altered suggest that maladaptations to mitochondrial dysfunction may underpin disease pathology. We hypothesized that the severity of this maladaptation could be shaped by the plasticity of the system when mitochondrial dysfunction manifests. To investigate this, we have used inducible fly models of mitochondrial complex I (CI) dysfunction to reduce mitochondrial function at two stages of the fly lifecycle, from early development and adult eclosion. Here, we show that in early life (developmental) mitochondrial dysfunction results in severe reductions in survival and stress resistance in adulthood, while flies where mitochondrial function is perturbed from adulthood, are long-lived and stress resistant despite having up to a 75% reduction in CI activity. After excluding developmental defects as a cause, we went on to molecularly characterize these two populations of mitochondrially compromised flies, short- and long-lived. We find that our short-lived flies have unique transcriptomic, proteomic and metabolomic responses, which overlap significantly in discrete models of CI dysfunction. Our data demonstrate that early mitochondrial dysfunction via CI depletion elicits a maladaptive response, which severely reduces survival, while CI depletion from adulthood is insufficient to reduce survival and stress resistance.
    Keywords:  Ageing; Complex I; Drosophila; Mitochondria; Mitochondrial Disease
    DOI:  https://doi.org/10.1038/s44319-025-00416-6
  7. Mol Med. 2025 Mar 15. 31(1): 102
    miR-27a-5p, miR-21-5p, miR-1246 and miR-4508: a candidate microRNA signature in the protection and regulation of viral infection in mild COVID-19.
    Malena Gajate-Arenas, Candela Sirvent-Blanco, Omar García-Pérez, Angélica Domínguez-de-Barros, José E Piñero, Jacob Lorenzo-Morales, Elizabeth Córdoba-Lanús.
      MicroRNAs (miRNAs) are gene regulators essential for cell homeostasis, their alteration is related to a pathological state, including infectious diseases like COVID-19. Identifying an altered profile of circulating miRNAs in mild COVID-19 may enhance our knowledge of the pathogenesis of SARS-CoV-2 and the range of clinical phenotypes. In the present study, a miRNA screening was performed by Next Generation Sequencing (NGS), and the expression levels of 13 resulting miRNAs were validated through RT-qPCR in the serum of 40 mild cases compared to 29 non-infected individuals. An in-silico analysis was performed to detect target genes and their related pathways. From the validated miRNAs, miR-1246 (p < 0.001), miR-423-5p (p < 0.001), miR-21-5p (p = 0.005), miR-146a-5p (p < 0.001), miR-4508 (p = 0.001), miR-629-5p (p < 0.001), and miR-210-3p (p = 0.002) were found downregulated in infected individuals. Only miR-27a-5p was overexpressed in subjects with COVID-19 (p = 0.013) and associated with SARS-CoV-2 infection (p = 0.010). The KEGG pathways and GO analysis revealed that the differentially expressed miRNAs were related to viral processes or immunological pathways: miR-27a-5p acts on the TGF-beta pathway; miR-21-5p targets SMAD7, which is associated with the inflammatory response in the lung; miR-1246 acts on p53 pathway; and miR-4508 acts on ICAM2. In conclusion, the most relevant miRNAs, miR-27a-5p and miR-21-5p, were differently expressed in mild forms of COVID-19. The higher expression of miR-27a-5p observed in mild COVID-19 cases may suggest a protective effect against severe forms of the disease. Reduced expression of miR-21-5p may prevent pulmonary inflammation and the progression of fibrosis. The downregulation of miR-1246 and miR-4508 in mild COVID-19 cases may conduct the correct control of the infection. Moreover, miR-423-5p might be a suitable biomarker in the early stages of SARS-CoV-2 infection.
    DOI:  https://doi.org/10.1186/s10020-025-01154-0
  8. Acta Neurol Belg. 2025 Mar 18.
    Circulating miR-223/NLRP3 axis and IL-1β level in functional disease progression of amyotrophic lateral sclerosis.
    Mitra Ansari Dezfouli, Davood Shalilahmadi, Gholamreza Shamsaei, Ashkan Esmaeili, Nastaran Majdinasab, Seyed Khalil Rashidi.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease identified by progressive motor neuron loss. NLRP3 inflammasomes induce inflammation and pyroptosis, which can lead to neurodegeneration, muscle atrophy, and respiratory decline. miR-223 targets NLRP3 and suppresses inflammasome formation. Here, miR-223, NLRP3 and IL-1β levels were evaluated as plasma biomarkers in the incidence and progression of ALS.
    METHODS: 32 ALS patients and 32 healthy subjects were assessed. In all patients, the functional disability was determined by Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and the respiratory dysfunction was assessed by the percent predicted forced vital capacity (ppFVC) index in spirometry examination. Plasma levels of miR-223, NLRP3 and IL-1β were assessed in ALS and control groups.
    RESULTS: Compared to the healthy controls, ALS patients showed decreased miR-223 expression (P < 0.0001), increased NLRP3 expression (P = 0.0002) and increased IL-1β level (P = 0.0003). The areas under the ROC curves for miR-223, NLRP3 and IL-1β were 0.82, 0.76 and 0.75 respectively. The ALSFRS-R and ppFVC values were positively correlated with miR-223 and negatively correlated with NLRP3 and IL-1β levels.
    CONCLUSION: Our results indicated that changes in miR-223, NLRP3 and IL-1β levels may correlate with the occurrence and functional progression of ALS. Additionally, therapeutic approaches based on miR-223 and inflammatory mediators can be proposed as effective strategies against disease progression.
    Keywords:  Amyotrophic lateral sclerosis; Inflammasome; Interleukin-1 beta; MiR-223
    DOI:  https://doi.org/10.1007/s13760-025-02764-5
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