bims-musmir Biomed News
on microRNAs in muscle
Issue of 2025–03–09
eleven papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway
  1. Single-nuclei sequencing of skeletal muscle reveals subsynaptic-specific transcripts involved in neuromuscular junction maintenance.
  2. Skeletal Muscle: A Critical Organ for Survival and Recovery in Critical Illness.
  3. Phosphorylated tau 181 and 217 are elevated in serum and muscle of patients with amyotrophic lateral sclerosis.
  4. Immunosenescence in skeletal muscle: The role-play in cancer cachexia chessboard.
  5. Neuron-specific isoform of PGC-1α regulates neuronal metabolism and brain aging.
  6. Inhibition of ErbB2 mitigates secondary denervation after traumatic muscle injury.
  7. Epigenetic factors and inflammaging: FOXO3A as a potential biomarker of sarcopenia and upregulation of DNMT3A and SIRT3 in older adults.
  8. Joint damage is more severe following a single bout than multiple bouts of high magnitude loading in mice.
  9. Upregulation of MicroRNA-144 Suppresses Nrf2 Antioxidant Signaling Pathway in Patients with Severe COVID-19.
  10. Quantification of subcellular RNA localization through direct detection of RNA oxidation.
  11. Essential amino acids and branched-chain amino acids are associated with skeletal muscle and inflammatory parameters in older age.
  1. Nat Commun. 2025 Mar 05. 16(1): 2220
    Single-nuclei sequencing of skeletal muscle reveals subsynaptic-specific transcripts involved in neuromuscular junction maintenance.
    Alexander S Ham, Shuo Lin, Alice Tse, Marco Thürkauf, Timothy J McGowan, Lena Jörin, Filippo Oliveri, Markus A Rüegg.
      The neuromuscular junction (NMJ) is the synapse formed between motor neurons and skeletal muscle fibers. Its stability relies on the continued expression of genes in a subset of myonuclei, called NMJ myonuclei. Here, we use single-nuclei RNA-sequencing (snRNA-seq) to identify numerous NMJ-specific transcripts. To elucidate how the NMJ transcriptome is regulated, we also performed snRNA-seq on sciatic nerve transected, botulinum toxin injected, and Musk knockout muscles. The data show that NMJ gene expression is not only driven by agrin-Lrp4/MuSK signaling but is also affected by electrical activity and trophic factors other than agrin. By selecting the three NMJ genes Etv4, Lrtm1, and Pdzrn4, we further characterize novel contributors to NMJ stability and function. AAV-mediated overexpression shows that Etv4 is sufficient to upregulate the expression of -50% of the NMJ genes in non-synaptic myonuclei, while AAV-CRISPR/Cas9-mediated muscle-specific knockout of Pdzrn4 induces NMJ fragmentation. Further investigation of Pdzrn4 revealed that it localizes to the Golgi apparatus and interacts with MuSK protein. Collectively, our data provide a rich resource of NMJ transcripts, highlight the importance of ETS transcription factors at the NMJ, and suggest a novel pathway for NMJ post-translational modifications.
    DOI:  https://doi.org/10.1038/s41467-025-57487-1
  2. Crit Care Clin. 2025 Apr;pii: S0749-0704(24)00084-8. [Epub ahead of print]41(2): 299-312
    Skeletal Muscle: A Critical Organ for Survival and Recovery in Critical Illness.
    Matthew J Lees, Carla M Prado, Paul E Wischmeyer, Stuart M Phillips.
      The intensive care unit (ICU) environment is one of the most challenging for skeletal muscle health. Atrophy associated with clinical care is distinct from that seen with inactivity or immobilization in the absence of disease and is exacerbated by aging. The substantial muscle loss in the ICU is likely due to the presence of inflammation, elevated proteolysis, bedrest, and undernutrition. Skeletal muscle parameters at admission are predictive of mortality and other clinically important outcomes. Treatment goals to mitigate muscle loss are early mobilization and adequate nutrient supply, especially protein, using an individualized approach to support skeletal muscle maintenance and recovery.
    Keywords:  Amino acids; Atrophy; Bed rest; Immobilization; Intensive care unit; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.ccc.2024.08.011
  3. Nat Commun. 2025 Mar 05. 16(1): 2019
    Phosphorylated tau 181 and 217 are elevated in serum and muscle of patients with amyotrophic lateral sclerosis.
    Samir Abu-Rumeileh, Leila Scholle, Alexander Mensch, Henning Großkopf, Antonia Ratti, Anna Kölsch, Gisela Stoltenburg-Didinger, Julian Conrad, Anna De Gobbi, Lorenzo Barba, Petra Steinacker, Hans-Wolfgang Klafki, Patrick Oeckl, Steffen Halbgebauer, Caroline Stapf, Andreas Posa, Thomas Kendzierski, Vincenzo Silani, Lucrezia Hausner, Nicola Ticozzi, Lutz Froelich, Jochen Hans Weishaupt, Federico Verde, Markus Otto.
      Blood phosphorylated (p)-tau 181 and p-tau 217 have been proposed as accurate biomarkers of Alzheimer's disease (AD) pathology. However, blood p-tau 181 is also elevated in amyotrophic lateral sclerosis (ALS) without a clearly identified source. We measured serum p-tau 181 and p-tau 217 in a multicentre cohort of ALS (n = 152), AD (n = 111) cases and disease controls (n = 99) recruited from four different centres. Further, we investigated the existence of both p-tau species using immunohistochemistry (IHC) and mass spectrometry (MS) in muscle biopsies of ALS cases (IHC: n = 13, MS: n = 5) and disease controls (IHC: n = 14, MS: n = 5) from one cohort. Serum p-tau 181 and p-tau 217 were higher in AD and ALS patients compared to disease controls. IHC and MS analyses revealed the presence of p-tau 181 and 217 in muscle biopsies from both ALS cases and disease controls, with ALS samples showing increased p-tau reactivity in atrophic muscle fibres. Blood p-tau species could potentially be used to diagnose both ALS and AD.
    DOI:  https://doi.org/10.1038/s41467-025-57144-7
  4. Semin Cancer Biol. 2025 Feb 26. pii: S1044-579X(25)00040-9. [Epub ahead of print]111 48-59
    Immunosenescence in skeletal muscle: The role-play in cancer cachexia chessboard.
    Matteo Giovarelli, Emanuele Mocciaro, Carla Carnovale, Davide Cervia, Cristiana Perrotta, Emilio Clementi.
      With the increase in life expectancy, age-related conditions and diseases have become a widespread and relevant social burden. Among these, immunosenescence and cancer cachexia play a significant often intertwined role. Immunosenescence is the progressive aging decline of both the innate and adaptive immune systems leading to increased infection susceptibility, poor vaccination efficacy, autoimmune disease, and malignancies. Cancer cachexia affects elderly patients with cancer causing severe weight loss, muscle wasting, inflammation, and reduced response to therapies. Whereas the connections between immunosenescence and cancer cachexia have been raising attention, the molecular mechanisms still need to be completely elucidated. This review aims at providing the current knowledge about the interplay between immunosenescence, skeletal muscle, and cancer cachexia, analyzing the molecular pathways known so far to be involved. Finally, we highlight potential therapeutic strategies suited for elderly population aimed to block immunosenescence and to preserve muscle mass in cachexia, also presenting the analysis of the current state-of-the-art of related clinical trials.
    Keywords:  Cancer cachexia; Immune system; Immunosenescence; Sarcopenia; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.semcancer.2025.02.012
  5. Nat Commun. 2025 Feb 28. 16(1): 2053
    Neuron-specific isoform of PGC-1α regulates neuronal metabolism and brain aging.
    Dylan C Souder, Eric R McGregor, Josef P Clark, Timothy W Rhoads, Tiaira J Porter, Kevin W Eliceiri, Darcie L Moore, Luigi Puglielli, Rozalyn M Anderson.
      The brain is a high-energy tissue, and although aging is associated with dysfunctional inflammatory and neuron-specific functional pathways, a direct connection to metabolism is not established. Here, we show that isoforms of mitochondrial regulator PGC-1α are driven from distinct brain cell-type specific promotors, repressed with aging, and integral in coordinating metabolism and growth signaling. Transcriptional and proteomic profiles of cortex from male adult, middle age, and advanced age mice reveal an aging metabolic signature linked to PGC-1α. In primary culture, a neuron-exclusive promoter produces the functionally dominant isoform of PGC-1α. Using growth repression as a challenge, we find that PGC-1α is regulated downstream of GSK3β independently across promoters. Broad cellular metabolic consequences of growth inhibition observed in vitro are mirrored in vivo, including activation of PGC-1α directed programs and suppression of aging pathways. These data place PGC-1α centrally in a growth and metabolism network directly relevant to brain aging.
    DOI:  https://doi.org/10.1038/s41467-025-57363-y
  6. J Physiol. 2025 Mar 03.
    Inhibition of ErbB2 mitigates secondary denervation after traumatic muscle injury.
    Jacob R Sorensen, Daniel B Hoffman, Christiana J Raymond-Pope, Thomas J Lillquist, Amanda M Russell, Benjamin T Corona, Sarah M Greising.
      Secondary denervation has recently been described as part of the sequela of volumetric muscle loss (VML) injury, occurring along with a significantly elevated neurotrophic response, specifically neuregulin-1 (NRG1). This may contribute to chronic functional impairments associated with the injury, representing an overlooked treatment target. Thus, though paradoxical, the goal of this study was to pharmacologically reduce neurotrophic signalling after VML using a monoclonal antibody (Herceptin) that inhibits ErbB2 receptors. We also assessed whether ErbB2 inhibition combined with a myogenic treatment (i.e. minced muscle graft) would have a synergistically beneficial effect on function. Adult male Lewis rats underwent surgical induction of tibialis anterior muscle VML injury and were randomized into one of four groups: VML untreated, VML Herceptin, VML muscle graft and VML muscle graft + Herceptin, with comparisons to the contralateral (uninjured) control muscle. Rats receiving Herceptin were administered the drug (8 mg/kg i.p.) at the time of surgery and thrice per week for the duration of the study (48 days). Terminally individual NMJs were quantitatively evaluated, and maximal in vivo torque was tested. ErbB2 inhibition fully restored the normal rates of NMJ innervation and morphology after VML injury, and improved innervation of de novo myofibres after a muscle-graft treatment. However ErbB2 inhibition did not improve skeletal muscle function alone or in combination with a muscle-graft treatment. We conclude that ErbB2 inhibition is a promising therapeutic option for treating VML injury, yet more work is needed to optimize the translation of improved NMJ characteristics to recover function. KEY POINTS: In cases of complex traumatic musculoskeletal injury, such as volumetric muscle loss (VML), the endogenous ability of skeletal muscle to regenerate and recover function is lost. Innervation, or the connection of a motor axon to each individual myofibre, is a necessary component of myofibre survival and contractile function, which is disrupted after VML. Paradoxically a monocolonal antibody inhibitor of neurotrophic signalling (receptor tyrosine kinase ErbB2; Herceptin) has been shown to improve regeneration in rodent models of nerve injury. Here we show that pharmaceutical ErbB2 inhibition following a rat model of VML improves muscle innervation; however it did not correspondingly recover muscle function. Although ErbB2 inhibition alone is an ineffective treatment for VML injury, its ability to improve innervation is noteworthy and should be considered as an adjunctive or combinatorial therapy option.
    Keywords:  Herceptin; innervation; minced muscle graft; neuromuscular junction; volumetric muscle loss
    DOI:  https://doi.org/10.1113/JP287435
  7. Front Immunol. 2025 ;16 1467308
    Epigenetic factors and inflammaging: FOXO3A as a potential biomarker of sarcopenia and upregulation of DNMT3A and SIRT3 in older adults.
    Diana Bogucka, Anna Wajda, Barbara Stypińska, Marcin Jerzy Radkowski, Tomasz Targowski, Ewa Modzelewska, Tomasz Kmiołek, Adam Ejma-Multański, Gabriela Filipowicz, Yana Kaliberda, Ewa Dudek, Agnieszka Paradowska-Gorycka.
       Background: Epigenetic factors influence inflammaging and geriatric disorders such as sarcopenia and frailty. It is necessary to develop a biomarker/panel of biomarkers for fast and easy diagnostics. Currently, hard-to-access equipment is required to diagnose sarcopenia. The development of a biomarker/panel of biomarkers will prevent many older adults from being excluded from the diagnostic process.
    Methods: In this study, we analyzed selected gene expression profiles, namely, SIRT1, SIRT3, SIRT6, DNMT3A, FOXO1, FOXO3A, and ELAVL1, in whole blood. The study included 168 subjects divided into five groups: patients hospitalized at the Geriatrics Clinic and Polyclinic with sarcopenia, frailty syndrome, or without those disorders (geriatric control), and non-hospitalized healthy controls (HC) aged 25 to 30 years and over 50 years.
    Results: We revealed a lower mRNA level of FOXO3A (p<0.001) in sarcopenic patients compared to the geriatric controls. Furthermore, we detected upregulation of DNMT3A (p=0.003) and SIRT3 (p=0.015) in HC over 50 years old compared to HC aged 25 to 30 years. Interestingly, we observed 2 cluster formations during the gene expression correlation analysis (SIRT1, SIRT3, DNMT3A, and FOXO1, ELAVL1). We also noted correlations of clinical parameters with mRNA levels in the sarcopenic patients group, such as vitamin D level with SIRT1 (r=0.64, p=0.010), creatine kinase with SIRT3 (r=-0.58, p=0.032) and DNMT3A (r=-0.59, p=0.026), creatinine with DNMT3A (r=0.57, p=0.026), erythrocyte sedimentation rate (ESR) with FOXO3A (r=0.69, p=0.004), and lactate dehydrogenase (LDH) with FOXO3A (r=-0.86, p=0.007). In the frailty syndrome group, we noted a correlation of appendicular skeletal muscle mass (ASMM) with ELAVL1 (r=0.59, p=0.026) mRNA level. In the geriatric controls, we observed a correlation of serum iron with FOXO3A mRNA level (r=-0.79, p=0.036).
    Conclusions: Our study revealed FOXO3A as a potential biomarker of sarcopenia. Furthermore, we observed a high expression of epigenetic factors (DNMT3A and SIRT3) in older adults.
    Keywords:  DNMT3A; FOXO3A; SIRT3; ageing; frailty; geriatrics; inflammation; sarcopenia
    DOI:  https://doi.org/10.3389/fimmu.2025.1467308
  8. Osteoarthritis Cartilage. 2025 Feb 26. pii: S1063-4584(25)00821-0. [Epub ahead of print]
    Joint damage is more severe following a single bout than multiple bouts of high magnitude loading in mice.
    Sophia N Ziemian, Adrien Y Antoinette, Ana Witkowski, Miguel Otero, Steven R Goldring, Mary B Goldring, Marjolein C H van der Meulen.
       OBJECTIVE: While physiological loads maintain cartilage health, both joint overload and abnormal joint mechanical loading contribute to osteoarthritis (OA) development. Here, we examined the role of abnormal mechanical loading on joint health by comparing the severity of OA development following a single overload event and repetitive joint overloads.
    METHOD: Cyclic tibial compression was applied to the left limbs of 26-week-old male mice at a peak load of 9N for either a single bout or daily bouts to initiate OA disease. Joint damage severity was morphologically examined using histology and microcomputed tomography at 6 weeks following the start of loading. Early-stage transcriptomic responses to loading were evaluated.
    RESULTS: Joint damage was more severe at 6 weeks following a single bout of loading than after daily loading bouts. Severe cartilage damage, subchondral plate erosions, and soft tissue calcifications occurred following the single bout of loading. Daily loading bouts resulted in less severe cartilage damage and preserved subchondral plate integrity. A diverging transcriptomic response was identified in cartilage at 1 week with increased expression of fibrosis- and inflammation-related genes following a single bout of loading compared to daily loading.
    CONCLUSIONS: Even applied at hyperphysiological load magnitudes known to initiate cartilage damage, repetitive loading may induce protective effects in the joint and attenuate OA progression over time relative to a single bout of loading. Our findings suggest the potential of mechanotherapies that use repetitive loading as disease-modifying treatments for OA disease.
    Keywords:  Mechanical loading; Osteoarthritis; Pre-clinical model; Transcriptomics
    DOI:  https://doi.org/10.1016/j.joca.2025.01.006
  9. Iran J Allergy Asthma Immunol. 2025 Feb 13. 24(1): 31-40
    Upregulation of MicroRNA-144 Suppresses Nrf2 Antioxidant Signaling Pathway in Patients with Severe COVID-19.
    Mahdieh Nasirzadeh, Mahdi Pouramir, Shiva Gholizadeh-Ghaleh Aziz, Shahriar Alipour.
      MicroRNAs (miRs) play a pivotal role in the pathogenesis of viral infections. It has been proven that the Nrf2 (NFE2 like bZIP transcription factor 2) antioxidant signaling pathway is inhibited in COVID-19 patients. Two microRNAs (MIR144 and MIR153-1) have been identified as important Nrf2 regulators. The aim of this study was to analyze the MIR144 and MIR153-1 expression in COVID-19 patients and investigate their association with the Nrf2 signaling pathway. The study had 82 participants with both mild and severe COVID-19 manifestations and 25 healthy as a control group. Ficoll density-gradient centrifugation was used to separate peripheral blood mononuclear cells from ethylenediaminetetraacetic acid blood tubes. MIR144, MIR153-1, and NFE2L2 expressions were studied using real-time polymerase chain reaction. We employed the commercially available enzyme-linked immunosorbent assay to measure plasma Nrf2 protein concentration and the activity of antioxidant enzymes, superoxide dismutase, and catalase. Compared to the control group, MIR144 expression was significantly increased in the severe group, while NFE2L2 expression decreased. There was no significant difference in the MIR153-1 expression rate between COVID-19 patients and controls. Nrf2 protein and antioxidant enzyme activity significantly decreased in the severe group. A negative correlation between MIR144 expression and Nrf2 protein concentration was observed. Taken together, the current study's findings showed that MIR144 upregulation probably interferes with the Nrf2 antioxidant signaling pathway in COVID-19 patients.
    Keywords:  COVID-19; MIR144; MIR153-1; Nrf2 Signaling pathway
    DOI:  https://doi.org/10.18502/ijaai.v24i1.18018
  10. Nucleic Acids Res. 2025 Feb 27. pii: gkaf139. [Epub ahead of print]53(5):
    Quantification of subcellular RNA localization through direct detection of RNA oxidation.
    Hei-Yong G Lo, Raeann Goering, Agnese Kocere, Joelle Lo, Megan C Pockalny, Laura K White, Haydee Ramirez, Abraham Martinez, Seth Jacobson, Robert C Spitale, Chad G Pearson, Marino J E Resendiz, Christian Mosimann, J Matthew Taliaferro.
      Across cell types and organisms, thousands of RNAs display asymmetric subcellular distributions. Studying this process requires quantifying abundances of specific RNAs at precise subcellular locations. To analyze subcellular transcriptomes, multiple proximity-based techniques have been developed in which RNAs near a localized bait protein are specifically labeled, facilitating their biotinylation and purification. However, these complex methods are often laborious and require expensive enrichment reagents. To streamline the analysis of localized RNA populations, we developed Oxidation-Induced Nucleotide Conversion sequencing (OINC-seq). In OINC-seq, RNAs near a genetically encoded, localized bait protein are specifically oxidized in a photo-controllable manner. These oxidation events are then directly detected and quantified using high-throughput sequencing and our software package, PIGPEN, without the need for biotin-mediated enrichment. We demonstrate that OINC-seq can induce and quantify RNA oxidation with high specificity in a dose- and light-dependent manner. We further show the spatial specificity of OINC-seq by using it to quantify subcellular transcriptomes associated with the cytoplasm, ER, nucleus, and the inner and outer membranes of mitochondria. Finally, using transgenic zebrafish, we demonstrate that OINC-seq allows proximity-mediated RNA labeling in live animals. In sum, OINC-seq together with PIGPEN provide an accessible workflow for analyzing localized RNAs across different biological systems.
    DOI:  https://doi.org/10.1093/nar/gkaf139
  11. Biogerontology. 2025 Mar 06. 26(2): 66
    Essential amino acids and branched-chain amino acids are associated with skeletal muscle and inflammatory parameters in older age.
    Ching Wah Donna Li, Catrin Herpich, Ulrike Haß, Bastian Kochlik, Daniela Weber, Tilman Grune, Kristina Norman.
      Aging is associated with a decline in muscle mass and function, increasing the risk of adverse health outcomes. Amino acid profiling has emerged as a potential tool for assessing skeletal muscle health. This study examines the associations between fasting plasma amino acids, muscle function, and inflammation in healthy older and young adults. Data from 131 participants (101 older adults, 71.5±4.9 years; 30 young adults, 25.5±3.9 years) were analyzed. Skeletal muscle mass was assessed using bioimpedance analysis, and hand grip strength was measured with a dynamometer. Plasma amino acids, kynurenine, and inflammatory markers (CRP, IL-6) were quantified using ultraperformance liquid chromatography with tandem mass spectrometry and commercial immunosorbent assays, respectively. Older adults exhibited lower levels of glutamic acid, isoleucine, leucine, phenylalanine, kynurenine, and kynurenine-to-tryptophan (KYN:TRP) ratio compared to younger individuals (all p<0.05). In older adults, branched-chain and essential amino acids correlated positively with skeletal muscle index (SMI) and hand grip strength, whereas in young adults, only glutamic acid, proline, and KYN:TRP showed positive associations with SMI (all p<0.05). CRP and IL-6 were associated with several amino acids in older adults but not in younger individuals. These findings suggest that age-related shifts in amino acid profiles may reflect underlying changes in muscle metabolism and function, highlighting their potential as early indicators of muscle decline.
    Keywords:  Aging; Amino acids; Inflammation; Metabolism; Muscle health; Sarcopenia
    DOI:  https://doi.org/10.1007/s10522-025-10206-1
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