bims-musmir Biomed News
on microRNAs in muscle
Issue of 2025–01–26
six papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway
  1. Age, cancer, and the dual burden of cancer and doxorubicin in skeletal muscle wasting in female rats: which one to blame?
  2. MicroRNA signatures of VO 2 peak in older adult participants of the Study of Muscle, Mobility and Aging.
  3. Whole blood transcriptome profile identifies motor neurone disease RNA biomarker signatures.
  4. mTOR Ser1261 is an AMPK-dependent phosphosite in mouse and human skeletal muscle not required for mTORC2 activity.
  5. Palmitate potentiates the SMAD3-PAI-1 pathway by reducing nuclear GDF15 levels.
  6. Induction of lysosome biogenesis is a novel function of the CGAS-STING1 pathway.
  1. Biogerontology. 2025 Jan 24. 26(1): 47
    Age, cancer, and the dual burden of cancer and doxorubicin in skeletal muscle wasting in female rats: which one to blame?
    Alexandra Moreira-Pais, Rita Ferreira, Inês Aires, Cláudia Sousa-Mendes, Rita Nogueira-Ferreira, Fernanda Seixas, Adelino Leite-Moreira, Paula A Oliveira, José A Duarte.
      Sarcopenia and cancer cachexia are two life-threatening conditions often misdiagnosed. The skeletal muscle is one of the organs most adversely affected by these conditions, culminating in poor quality of life and premature mortality. In addition, it has been suggested that chemotherapeutic agents exacerbate cancer cachexia, as is the case of doxorubicin. Herein, we sought to investigate markers of inflammation and neuromuscular junction (NMJ) remodeling during aging and in response to cancer or cancer with chemotherapy. To address this, we utilized female rats across three age groups - young, adult, and old - to examine age-related changes, with old rats serving as a sarcopenia model. Additionally, a chemically-induced breast cancer (BCa) model was implemented in female adult rats, both without (adult BCa) or with doxorubicin administration (adult BCaDOX), to study cancer cachexia. The atrophy of the gastrocnemius muscle was observed in old, adult BCa and adult BCaDOX rats compared to adult ones. No signs of inflammation or NMJ impairment were observed in adult BCa or adult BCaDOX rats, except for the low levels of the subunit α1 of the acetylcholine receptor in adult BCaDOX rats compared to adult ones. In contrast, old rats presented high serum levels of interleukin 6, brain-derived neurotrophic factor (BDNF) and calcitonin gene-related peptide compared to young rats. In the gastrocnemius muscle, BDNF levels were decreased in old rats compared to adult rats, suggesting impaired skeletal muscle regeneration upon age-induced damage. The BDNF muscle levels were inversely correlated with its levels in circulation in adult and old rats. Hence, this work highlights BDNF as a specific biomarker of age-induced skeletal muscle atrophy, at least, in the differential diagnosis against cancer- or cancer with chemotherapy-induced muscle wasting.
    Keywords:  Cachexia; Chemotherapy; Inflammation; Muscle atrophy; Neuromuscular junction; Sarcopenia
    DOI:  https://doi.org/10.1007/s10522-024-10182-y
  2. bioRxiv. 2025 Jan 08. pii: 2025.01.08.631999. [Epub ahead of print]
    MicroRNA signatures of VO 2 peak in older adult participants of the Study of Muscle, Mobility and Aging.
    Genesio M Karere, Fang-Chi Hsu, Russell T Hepple, Paul M Coen, Steve Cummings, Anne Newman, Nancy W Glynn, Lauren Sparks, Nancy E Lane, Jianzhao Xu, Nathan Wagner, Ge Li, Jeanne Chan, Laura A Cox, Stephen Kritchevsky.
       Background: Peak oxygen consumption during exercise (VO 2 peak), is a direct measure of cardiorespiratory fitness (CF), a key indicator of physical function and overall health. However, the molecular changes that underpin VO 2 peak variation are not clear. Our objective is to understand the miRNA signatures that relate to VO 2 peak variation, which could provide insights to novel mechanisms that contribute to low VO 2 peak.
    Methods: We used small RNA sequencing to analyze serum samples from 72 participants (70-79 yrs old, 53% female) of the Study of Muscle, Mobility and Aging (SOMMA). We analyzed samples from individuals with low or high VO 2 peak (N=18/group) as well as samples from 36 randomly selected participants spanning the entire spectrum of VO 2 peak. We used LIMMA analysis package for regression analysis and to identify differentially expressed miRNAs. We used receiver operating characteristic curve analysis to evaluate the Area Under the Curve (AUC) and sensitivity and specificity rates.
    Results: We identified 1,055 miRNAs expressed in all serum samples. Expression of 65 miRNAs differed between participants with low and high VO 2 peak (p < 0.05). After p-value adjustment, expression of 5 miRNAs (miR-1301-3p, -431-5p, -501-5p, -519a-3p, and -18a-3p) remained significantly different (FDR = 0.05). The five miRNAs had AUC ranging from 0.77 to 0.84. The optimal sensitivity and specificity ranged from 70 to 80% and 80 to 90%, respectively. After adjustment for age and sex covariates, 46 miRNAs significantly correlated with VO 2 peak (p < 0.05) and miR-519a-3p remained significant based on adjusted of p-values.
    Conclusions: We identified a miRNA signature of VO 2 peak in older individuals that might provide insights to novel mechanisms that drive low VO 2 peak. Future studies will validate the findings in a larger, longitudinal study cohort.
    DOI:  https://doi.org/10.1101/2025.01.08.631999
  3. Exp Biol Med (Maywood). 2024 ;249 10401
    Whole blood transcriptome profile identifies motor neurone disease RNA biomarker signatures.
    Sulev Kõks, Karin Rallmann, Mari Muldmaa, Jack Price, Abigail L Pfaff, Pille Taba.
      Blood-based biomarkers for motor neuron disease are needed for better diagnosis, progression prediction, and clinical trial monitoring. We used whole blood-derived total RNA and performed whole transcriptome analysis to compare the gene expression profiles in (motor neurone disease) MND patients to the control subjects. We compared 42 MND patients to 42 aged and sex-matched healthy controls and described the whole transcriptome profile characteristic for MND. In addition to the formal differential analysis, we performed functional annotation of the genomics data and identified the molecular pathways that are differentially regulated in MND patients. We identified 12,972 genes differentially expressed in the blood of MND patients compared to age and sex-matched controls. Functional genomic annotation identified activation of the pathways related to neurodegeneration, RNA transcription, RNA splicing and extracellular matrix reorganisation. Blood-based whole transcriptomic analysis can reliably differentiate MND patients from controls and can provide useful information for the clinical management of the disease and clinical trials.
    Keywords:  RNA-seq; amyotrophic lateral sclerosis; gene expression profiling; motor neuron disease; whole transcriptome
    DOI:  https://doi.org/10.3389/ebm.2024.10401
  4. FASEB J. 2025 Jan 31. 39(2): e70277
    mTOR Ser1261 is an AMPK-dependent phosphosite in mouse and human skeletal muscle not required for mTORC2 activity.
    Jingwen Li, Agnete B Madsen, Jonas R Knudsen, Carlos Henriquez-Olguin, Kaspar W Persson, Zhencheng Li, Steffen H Raun, Tianjiao Li, Bente Kiens, Jørgen F P Wojtaszewski, Erik A Richter, Leonardo Nogara, Bert Blaauw, Riki Ogasawara, Thomas E Jensen.
      The kinases AMPK, and mTOR as part of either mTORC1 or mTORC2, are major orchestrators of cellular growth and metabolism. Phosphorylation of mTOR Ser1261 is reportedly stimulated by both insulin and AMPK activation and a regulator of both mTORC1 and mTORC2 activity. Intrigued by the possibilities that Ser1261 might be a convergence point between insulin and AMPK signaling in skeletal muscle, we investigated the regulation and function of this site using a combination of human exercise, transgenic mouse, and cell culture models. Ser1261 phosphorylation on mTOR did not respond to insulin in any of our tested models, but instead responded acutely to contractile activity in human and mouse muscle in an AMPK activity-dependent manner. Contraction-stimulated mTOR Ser1261 phosphorylation in mice was decreased by Raptor muscle knockout (mKO) and increased by Raptor muscle overexpression, yet was not affected by Rictor mKO, suggesting most of Ser1261 phosphorylation occurs within mTORC1 in skeletal muscle. In accordance, HEK293 cells mTOR Ser1261Ala mutation strongly impaired phosphorylation of mTORC1 substrates but not mTORC2 substrates. However, neither mTORC1 nor mTORC2-dependent phosphorylations were affected in muscle-specific kinase-dead AMPK mice with no detectable mTOR Ser1261 phosphorylation in skeletal muscle. Thus, mTOR Ser1261 is an exercise but not insulin-responsive AMPK-dependent phosphosite in human and murine skeletal muscle, playing an unclear role in mTORC1 regulation but clearly not required for mTORC2 activity.
    Keywords:  AMPK; exercise; mTORC1; mTORC2; skeletal muscle
    DOI:  https://doi.org/10.1096/fj.202402064R
  5. Cell Mol Life Sci. 2025 Jan 18. 82(1): 43
    Palmitate potentiates the SMAD3-PAI-1 pathway by reducing nuclear GDF15 levels.
    Marta Montori-Grau, Emma Barroso, Javier Jurado-Aguilar, Mona Peyman, Walter Wahli, Xavier Palomer, Manuel Vázquez-Carrera.
      Nuclear growth differentiation factor 15 (GDF15) reduces the binding of the mothers' against decapentaplegic homolog (SMAD) complex to its DNA-binding elements. However, the stimuli that control this process are unknown. Here, we examined whether saturated fatty acids (FA), particularly palmitate, regulate nuclear GDF15 levels and the activation of the SMAD3 pathway in human skeletal myotubes and mouse skeletal muscle, where most insulin-stimulated glucose use occurs in the whole organism. Human LHCN-M2 myotubes and skeletal muscle from wild-type and Gdf15-/- mice fed a standard (STD) or a high-fat (HFD) diet were subjected to a series of studies to investigate the involvement of lipids in nuclear GDF15 levels and the activation of the SMAD3 pathway. The saturated FA palmitate, but not the monounsaturated FA oleate, increased the expression of GDF15 in human myotubes and, unexpectedly, decreased its nuclear levels. This reduction was prevented by the nuclear export inhibitor leptomycin B. The decrease in nuclear GDF15 levels caused by palmitate was accompanied by increases in SMAD3 protein levels and in the expression of its target gene SERPINE1, which encodes plasminogen activator inhibitor 1 (PAI-1). HFD-fed Gdf15-/- mice displayed aggravated glucose intolerance compared to HFD-fed WT mice, with increased levels of SMAD3 and PAI-1 in the skeletal muscle. The increased PAI-1 levels in the skeletal muscle of HFD-fed Gdf15-/- mice were accompanied by a reduction in one of its targets, hepatocyte growth factor (HGF)α, a cytokine involved in glucose metabolism. Interestingly, PAI-1 acts as a ligand of signal transducer and activator of transcription 3 (STAT3) and the phosphorylation of this transcription factor was exacerbated in HFD-fed Gdf15-/- mice compared to HFD-fed WT mice. At the same time, the protein levels of insulin receptor substrate 1 (IRS-1) were reduced. These findings uncover a potential novel mechanism through which palmitate induces the SMAD3-PAI-1 pathway to promote insulin resistance in skeletal muscle by reducing nuclear GDF15 levels.
    Keywords:  GDF15; Insulin resistance; Muscle; Oleate; PAI-1; Palmitate; SMAD3
    DOI:  https://doi.org/10.1007/s00018-024-05571-y
  6. Autophagy. 2025 Jan 21.
    Induction of lysosome biogenesis is a novel function of the CGAS-STING1 pathway.
    Yinfeng Xu, Wei Wan.
      Induction of macroautophagy/autophagy has been established as an important function elicited by the CGAS-STING1 pathway during pathogen infection. However, it remains unknown whether lysosomal activity within the cell in these settings is concurrently enhanced to cope with the increased autophagic flux. Recently, we discovered that the CGAS-STING1 pathway elevates the degradative capacity of the cell by activating lysosome biogenesis. Intriguingly, we found that STING1-induced GABARAP lipidation, rather than TBK1 activation, serves as the key mediator triggering the nuclear translocation of transcription factor TFEB and enhances the expression of lysosome-related genes. Mechanistically, we demonstrated that lipidated GABARAP on single membranes, regulated by the V-ATPase-ATG16L1 axis, sequesters the FLCN-FNIP complex to abolish its function toward RRAGC-RRAGD, leading to a specific impairment of MTORC1-dependent phosphorylation of TFEB and resulting in its subsequent nuclear translocation. Functionally, we showed that STING1-induced lysosome biogenesis is essential for the clearance of cytoplasmic DNA and the elimination of invading pathogens. Collectively, our findings underscore the induction of lysosome biogenesis as a novel function of the CGAS-STING1 pathway.China; Yinfeng Xu; Email: yinfengxu@hnfnu.edu.cn; Hunan First Normal University, 1015 Feng-Lin-San Road, Changsha, Hunan 410,205, China.
    Keywords:  Autophagy; CGAS; GABARAP; STING1; TFEB; lysosome
    DOI:  https://doi.org/10.1080/15548627.2025.2456064
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