bims-musmir Biomed News
on microRNAs in muscle
Issue of 2024–11–10
six papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway
  1. NAD+: An Old but Promising Therapeutic Agent for Skeletal Muscle Ageing.
  2. Cellular ATP demand creates metabolically distinct subpopulations of mitochondria.
  3. SMN depletion impairs skeletal muscle formation and maturation in a mouse model of SMA.
  4. Data normalization of plasma miRNA profiling from patients with COVID-19.
  5. The combined influences of local heat application and resistance exercise on the acute mRNA response of skeletal muscle.
  6. Motor unit adaptation to disuse: crossing the threshold from firing rate suppression to neuromuscular junction transmission.
  1. Ageing Res Rev. 2023 Oct 28. pii: S1568-1637(23)00265-9. [Epub ahead of print] 102106
    NAD+: An Old but Promising Therapeutic Agent for Skeletal Muscle Ageing.
    Yingying Xu, Weihua Xiao.
      More than a century after the discovery of nicotinamide adenine dinucleotide (NAD+), our understanding of the molecule's role in the biology of ageing continues to evolve. As a coenzyme or substrate for many enzymes, NAD+ governs a wide range of biological processes, including energy metabolism, genomic stability, signal transduction, and cell fate. NAD+ deficiency has been recognised as a bona fide hallmark of tissue degeneration, and restoring NAD+ homeostasis helps to rejuvenate multiple mechanisms associated with tissue ageing. The progressive loss of skeletal muscle homeostasis with age is directly associated with high morbidity, disability and mortality. The aetiology of skeletal muscle ageing is complex, involving mitochondrial dysfunction, senescence and stem cell depletion, autophagy defects, chronic cellular stress, intracellular ion overload, immune cell dysfunction, circadian clock disruption, microcirculation disorders, persistent denervation, and gut microbiota dysbiosis. This review focuses on the therapeutic potential of NAD+ restoration to alleviate the above pathological factors and discusses the effects of in vivo administration of different NAD+ boosting strategies on skeletal muscle homeostasis, aiming to provide a reference for combating skeletal muscle ageing.
    Keywords:  NAD(+) boosting; NAD(+) metabolism; Skeletal muscle ageing; Therapies
    DOI:  https://doi.org/10.1016/j.arr.2023.102106
  2. Nature. 2024 Nov 06.
    Cellular ATP demand creates metabolically distinct subpopulations of mitochondria.
    Keun Woo Ryu, Tak Shun Fung, Daphne C Baker, Michelle Saoi, Jinsung Park, Christopher A Febres-Aldana, Rania G Aly, Ruobing Cui, Anurag Sharma, Yi Fu, Olivia L Jones, Xin Cai, H Amalia Pasolli, Justin R Cross, Charles M Rudin, Craig B Thompson.
      Mitochondria serve a crucial role in cell growth and proliferation by supporting both ATP synthesis and the production of macromolecular precursors. Whereas oxidative phosphorylation (OXPHOS) depends mainly on the oxidation of intermediates from the tricarboxylic acid cycle, the mitochondrial production of proline and ornithine relies on reductive synthesis1. How these competing metabolic pathways take place in the same organelle is not clear. Here we show that when cellular dependence on OXPHOS increases, pyrroline-5-carboxylate synthase (P5CS)-the rate-limiting enzyme in the reductive synthesis of proline and ornithine-becomes sequestered in a subset of mitochondria that lack cristae and ATP synthase. This sequestration is driven by both the intrinsic ability of P5CS to form filaments and the mitochondrial fusion and fission cycle. Disruption of mitochondrial dynamics, by impeding mitofusin-mediated fusion or dynamin-like-protein-1-mediated fission, impairs the separation of P5CS-containing mitochondria from mitochondria that are enriched in cristae and ATP synthase. Failure to segregate these metabolic pathways through mitochondrial fusion and fission results in cells either sacrificing the capacity for OXPHOS while sustaining the reductive synthesis of proline, or foregoing proline synthesis while preserving adaptive OXPHOS. These findings provide evidence of the key role of mitochondrial fission and fusion in maintaining both oxidative and reductive biosyntheses in response to changing nutrient availability and bioenergetic demand.
    DOI:  https://doi.org/10.1038/s41586-024-08146-w
  3. Hum Mol Genet. 2024 Nov 06. pii: ddae162. [Epub ahead of print]
    SMN depletion impairs skeletal muscle formation and maturation in a mouse model of SMA.
    Hong Liu, Lucia Chehade, Marc-Olivier Deguise, Yves De Repentigny, Rashmi Kothary.
      Spinal muscular atrophy (SMA) is characterized by low levels of the ubiquitously expressed Survival Motor Neuron (SMN) protein, leading to progressive muscle weakness and atrophy. Skeletal muscle satellite cells play a crucial role in muscle fiber maintenance, repair, and remodelling. While the effects of SMN depletion in muscle are well documented, its precise role in satellite cell function remains largely unclear. Using the Smn2B/- mouse model, we investigated SMN-depleted satellite cell biology through single fiber culture studies. Myofibers from Smn2B/- mice were smaller in size, shorter in length, had reduced myonuclear domain size, and reduced sub-synaptic myonuclear clusters-all suggesting impaired muscle function and integrity. These changes were accompanied by a reduction in the number of myonuclei in myofibers from Smn2B/- mice across all disease stages examined. Although the number of satellite cells in myofibers was significantly reduced, those remaining retained their capacity for myogenic activation and proliferation. These findings support the idea that a dysregulated myogenic process could be occurring as early in muscle stem cells during muscle formation and maturation in SMA. Targeting those pathways could offer additional options for combinatorial therapies for SMA.
    Keywords:  muscle satellite cells; myofiber; myonuclear domain; single fiber culture
    DOI:  https://doi.org/10.1093/hmg/ddae162
  4. Sci Rep. 2024 11 05. 14(1): 26791
    Data normalization of plasma miRNA profiling from patients with COVID-19.
    Julia Tiemi Siguemoto, Carolini Motta Neri, Nadine de Godoy Torso, Aline de Souza Nicoletti, Marília Berlofa Visacri, Carla Regina da Silva Correa da Ronda, Mauricio Wesley Perroud, Leonardo Oliveira Reis, Luiz Augusto Dos Santos, Nelson Durán, Wagner José Fávaro, Eder de Carvalho Pincinato, Patricia Moriel.
      When using the reverse-transcription quantitative polymerase chain reaction (RT-qPCR) technique for quantitative assessment of microRNA (miRNA) expression, normalizing data using a stable endogenous gene is essential; however, no universally adequate reference gene exists. Therefore, in this study, we aimed to determine, via the RNA-Seq technique, the most adequate endogenous normalizer for the expression assessment of plasma miRNAs in patients with coronavirus disease 2019 (COVID-19). Two massive sequencing procedures were performed (a) to identify differentially expressed miRNAs between patients with COVID-19 and healthy volunteers (n = 12), and (b) to identify differentially expressed miRNAs between patients with severe COVID-19 and those with mild COVID-19 (n = 8). The endogenous normalizer candidates were selected according to the following criteria: (1) the miRNA must have a fold regulation = 1; (2) the miRNA must have a p-value > 0.990; and (3) the miRNAs that were discovered the longest ago should be selected. Four miRNAs (hsa-miR-34a-3p, hsa-miR-194-3p, hsa-miR-17-3p, and hsa-miR-205-3p) met all criteria and were selected for validation by RT-qPCR in a cohort of 125 patients. Of these, only hsa-miR-205-3p was eligible endogenous normalizers in the context of COVID-19 because their expression was stable between the compared groups.
    Keywords:  COVID-19; Endogenous normalizer; MicroRNA; Reference gene
    DOI:  https://doi.org/10.1038/s41598-024-75740-3
  5. Front Physiol. 2024 ;15 1473241
    The combined influences of local heat application and resistance exercise on the acute mRNA response of skeletal muscle.
    Mark L McGlynn, Alejandro M Rosales, Christopher W Collins, Dustin R Slivka.
       Introduction: The development and maintenance of the skeletal muscle is crucial for the support of daily function. Heat, when applied locally, has shown substantial promise in the maintenance of the muscle. The purpose of this study was to determine the combined effects of local heat application and acute resistance exercise on gene expression associated with the human muscle growth program.
    Materials and methods: Participants (n = 12, 26 ± 7 years, 1.77 ± 0.07 m, 79.6 ± 15.4 kg, and 16.1 ± 11.6 %BF) completed an acute bilateral bout of resistance exercise consisting of leg press (11 ± 2 reps; 170 ± 37 kg) and leg extension (11 ± 1 reps; 58 ± 18 kg). Participants wore a thermal wrap containing circulating fluid (40°C, exercise + heat; EX + HT) during the entire experimental period and 4 h post-exercise, while the other leg served as an exercise-only (EX) control. Biopsies of the vastus lateralis were collected (Pre, Post, and 4hPost) for gene expression analyses.
    Results: Intramuscular temperatures increased (Post, +2.2°C ± 0.7°C, and p < 0.001; 4hPost, +2.5°C ± 0.6°C, and p < 0.001) and were greater in the EX + HT leg post-exercise (+0.35°C ± 0.3°C, and p = 0.005) and after 4hPost (+2.1°C ± 0.8°C and p < 0.001). MYO-D1 mRNA was greater in the EX + HT leg vs. the EX (fold change = 2.74 ± 0.42 vs. 1.70 ± 0.28, p = 0.037). No other genes demonstrated temperature sensitivity when comparing both legs (p > 0.05). mRNA associated with the negative regulator, myostatin (MSTN), decreased post-exercise (p = 0.001) and after 4 h (p = 0.001). mRNA associated with proteolysis decreased post-exercise (FBXO32, p = 0.001; FOXO3a, p = 0.001) and after 4 h (FBXO32, p = 0.001; FOXO3a, p = 0.027).
    Conclusion: The elevated transcription of the myogenic differentiation factor 1 (MYO-D1) after exercise in the heated condition may provide a mechanism by which muscle growth could be enhanced.
    Keywords:  gene expression; myogenic; myogenic differentiation factor 1; myogenin; myostatin; proteolytic
    DOI:  https://doi.org/10.3389/fphys.2024.1473241
  6. J Physiol. 2024 Nov 04.
    Motor unit adaptation to disuse: crossing the threshold from firing rate suppression to neuromuscular junction transmission.
    Mathew Piasecki.
      Neural conditioning to scenarios of muscle disuse is undoubtedly a cause of functional decrements that typically exceed losses of muscle size. Yet establishing the relative contribution of neural adaptation and the specific location in the motor pathway remains technically challenging. Several studies of healthy humans have targeted this system and have established that motor unit firing rate is suppressed following disuse, with a number of critical caveats. It is suppressed in the immobilized limb only, at relative and absolute force levels, and preferentially targets lower-threshold motor units. Concomitantly, electrophysiological investigation of neuromuscular junction transmission (NMJ) stability of lower-threshold motor units reveals minimal change following disuse. These findings contrast with numerous other methods, which show clear involvement of the NMJ but are unable to characterize the motor unit to which they belong. It is physiologically plausible that decrements observed following disuse are a result of suppressed firing rate of lower-threshold motor units and impairment of transmission of the NMJ of higher-threshold motor units. As such, motor units within the pool should be viewed in light of their varying susceptibility to disuse.
    Keywords:  disuse; firing rate; motoneuron; neuromuscular junction
    DOI:  https://doi.org/10.1113/JP284159
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