bims-musmir Biomed News
on microRNAs in muscle
Issue of 2024–08–18
six papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway
  1. microRNA-1 Regulates Metabolic Flexibility in Skeletal Muscle via Pyruvate Metabolism.
  2. The Diversity of Skeletal Muscle Fiber Types.
  3. Autophagy in Skeletal Muscle.
  4. RBM5 induces motor neuron apoptosis in hSOD1G93A-related amyotrophic lateral sclerosis by inhibiting Rac1/AKT pathways.
  5. A ketogenic diet, regardless of fish oil content, does not affect glucose homeostasis or muscle insulin response in male rats.
  6. BK channels promote action potential repolarization in skeletal muscle but contribute little to myotonia.
  1. bioRxiv. 2024 Aug 10. pii: 2024.08.09.607377. [Epub ahead of print]
    microRNA-1 Regulates Metabolic Flexibility in Skeletal Muscle via Pyruvate Metabolism.
    Ahmed Ismaeel, Bailey D Peck, McLane M Montgomery, Benjamin I Burke, Jensen Goh, Gyumin Kang, Abigail B Franco, Qin Xia, Katarzyna Goljanek-Whysall, Brian McDonagh, Jared M McLendon, Pieter J Koopmans, Daniel Jacko, Kirill Schaaf, Wilhelm Bloch, Sebastian Gehlert, Yuan Wen, Kevin A Murach, Charlotte A Peterson, Ryan L Boudreau, Kelsey H Fisher-Wellman, John J McCarthy.
      MicroRNA-1 (miR-1) is the most abundant miRNA in adult skeletal muscle. To determine the function of miR-1 in adult skeletal muscle, we generated an inducible, skeletal muscle-specific miR-1 knockout (KO) mouse. Integration of RNA-sequencing (RNA-seq) data from miR-1 KO muscle with Argonaute 2 enhanced crosslinking and immunoprecipitation sequencing (AGO2 eCLIP-seq) from human skeletal muscle identified miR-1 target genes involved with glycolysis and pyruvate metabolism. The loss of miR-1 in skeletal muscle induced cancer-like metabolic reprogramming, as shown by higher pyruvate kinase muscle isozyme M2 (PKM2) protein levels, which promoted glycolysis. Comprehensive bioenergetic and metabolic phenotyping combined with skeletal muscle proteomics and metabolomics further demonstrated that miR-1 KO induced metabolic inflexibility as a result of pyruvate oxidation resistance. While the genetic loss of miR-1 reduced endurance exercise performance in mice and in C. elegans, the physiological down-regulation of miR-1 expression in response to a hypertrophic stimulus in both humans and mice causes a similar metabolic reprogramming that supports muscle cell growth. Taken together, these data identify a novel post-translational mechanism of adult skeletal muscle metabolism regulation mediated by miR-1.
    DOI:  https://doi.org/10.1101/2024.08.09.607377
  2. Cold Spring Harb Perspect Biol. 2024 Aug 12. pii: a041477. [Epub ahead of print]
    The Diversity of Skeletal Muscle Fiber Types.
    Stefano Schiaffino, Francesco Chemello, Carlo Reggiani.
      The widespread presence of slow-red and fast-white muscles in all vertebrates supports the evolutionary advantage of having two types of motors available for animal movement-a slow economical motor used for most activities, and a fast energetically costly motor used for rapid movements and emergency actions, and actions that require a lot of force. Skeletal muscles are composed of multiple fiber types whose structural and functional properties have only in part been characterized. Further progress in this field is mainly occurring along two directions: Multiomics approaches are providing a global picture of the molecular composition of muscle fibers up to the single fiber and single nucleus level. Signaling studies are identifying many transcription factors and pathways controlling fiber-type specification. These new data should now be integrated into a wider whole-body context by defining the matching between muscle fiber and motor neuron heterogeneity in the neuromuscular system, as well as the relevance of muscle fiber types in systemic homeostatic functions, including metabolism and thermogenesis.
    DOI:  https://doi.org/10.1101/cshperspect.a041477
  3. Cold Spring Harb Perspect Biol. 2024 Aug 12. pii: a041565. [Epub ahead of print]
    Autophagy in Skeletal Muscle.
    Anais Franco-Romero, Marco Sandri, Stefano Schiaffino.
      Skeletal muscle fibers possess, like all cells of our body, an evolutionary conserved autophagy machinery, which allows them to segregate unfolded proteins and damaged organelles within autophagosomes, and to induce fusion of autophagosomes with lysosomes, leading to degradation of those altered cell constituents. This process may be selective for specific cell components, as in the case of glycogen (glycophagy) or organelles, as with mitochondria (mitophagy). The autophagic flux is activated by fasting, and contributes with the proteasome to provide the organism with amino acids required for survival. Autophagy is also essential for the normal turnover of muscle proteins and organelles, as shown by the degenerative changes induced by genetic block of the autophagic mechanism, and in several myopathies. Autophagy is enhanced in muscle by exercise and impaired during aging, suggesting that aging-dependent muscle dysfunction could be delayed by boosting autophagy.
    DOI:  https://doi.org/10.1101/cshperspect.a041565
  4. Brain Res Bull. 2024 Aug 12. pii: S0361-9230(24)00182-5. [Epub ahead of print] 111049
    RBM5 induces motor neuron apoptosis in hSOD1G93A-related amyotrophic lateral sclerosis by inhibiting Rac1/AKT pathways.
    Xingli Tan, Xiaoli Su, Ying Wang, Weiwei Liang, Di Wang, Di Huo, Hongyong Wang, Yan Qi, Wenmo Zhang, Ling Han, Dongmei Zhang, Ming Wang, Jing Xu, Honglin Feng.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder distinguished by gradual depletion of motor neurons. RNA binding motif protein 5 (RBM5), an abundantly expressed RNA-binding protein, plays a critical role in the process of cellular death. However, little is known about the role of RBM5 in the pathogenesis of ALS. Here, we found that RBM5 was upregulated in ALS hSOD1G93A-NSC34 cell models and hSOD1G93A mice due to a reduction of miR-141-5p. The upregulation of RBM5 increased the apoptosis of motor neurons by inhibiting Rac1-mediated neuroprotection. In contrast, genetic knockdown of RBM5 rescued motor neurons from hSOD1G93A-induced degeneration by activating Rac1 signaling. The neuroprotective effect of RBM5-knockdown was significantly inhibited by the Rac1 inhibitor, NSC23766. These findings suggest that RBM5 could potentially serve as a therapeutic target in ALS by activating the Rac1 signalling.
    Keywords:  Amyotrophic lateral sclerosis; RBM5; apoptosis; miRNA
    DOI:  https://doi.org/10.1016/j.brainresbull.2024.111049
  5. Am J Physiol Endocrinol Metab. 2024 Aug 14.
    A ketogenic diet, regardless of fish oil content, does not affect glucose homeostasis or muscle insulin response in male rats.
    Joshua M Budd, Nicole M Notaro, Blair MacLeod, David M Mutch, David J Dyck.
      Ketogenic diets (KDs) are very high in fat and low in carbohydrates. Evidence supports that KDs improve glucose metabolism in humans and rodents that are obese and/or insulin resistant. Conversely, findings in healthy rodents suggest that KDs may impair glucose homeostasis. Additionally, most experimental KDs are composed of saturated and monounsaturated fatty acids, with almost no omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA). Evidence supports a beneficial role for n-3 LCPUFA on glucose homeostasis in the context of a metabolic challenge. To our knowledge, no study has examined whether the inclusion of n-3 LCPUFA affects the impact of a KD on glucose homeostasis. The objective of this study was to examine the impact of a KD on whole-body glucose tolerance and skeletal muscle insulin response in rats, and to determine if increasing the n-3 LCPUFA content in a KD with menhaden oil could improve metabolic outcomes. Male Sprague Dawley rats were pair-fed one of a low-fat diet, high-fat diet, KD, or a KD supplemented with menhaden oil (KDn-3) for 8 weeks. No significant differences in whole-body glucose tolerance, skeletal muscle insulin signaling, or skeletal muscle insulin-stimulated glucose uptake were detected between the dietary groups. Our findings suggest that KD feeding, with or without supplementation of n-3 LCPUFA, does not affect whole-body glucose homeostasis or skeletal muscle insulin response under pair-feeding conditions.
    Keywords:  glucose tolerance; insulin signaling; ketogenic diet; omega-3 fats; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpendo.00236.2024
  6. Pflugers Arch. 2024 Aug 16.
    BK channels promote action potential repolarization in skeletal muscle but contribute little to myotonia.
    Chris Dupont, Brianna Blake, Andrew A Voss, Mark M Rich.
      Patients with myotonia congenita suffer from slowed relaxation of muscle (myotonia), due to hyperexcitability caused by loss-of-function mutations in the ClC-1 chloride channel. A recent study suggested that block of large-conductance voltage- and Ca2+- activated K+ channels (BK) may be effective as therapy. The mechanism underlying efficacy was suggested to be lessening of the depolarizing effect of build-up of K+ in t-tubules of muscle during repetitive firing. BK channels are widely expressed in the nervous system and have been shown to play a central role in regulation of excitability, but their contribution to muscle excitability has not been determined. We performed intracellular recordings as well as force measurements in both wild type and BK-/- mouse extensor digitorum longus muscles. Action potential width was increased in BK-/- muscle due to slowing of repolarization, consistent with the possibility K+ build-up in t-tubules is lessened by block of BK channels in myotonic muscle. However, there was no difference in the severity of myotonia triggered by block of muscle Cl- channels with 9-anthracenecarboxylic acid (9AC) in wild type and BK-/- muscle fibers. Further study revealed no difference in the interspike membrane potential during repetitive firing suggesting there was no reduction in K+ build-up in t-tubules of BK-/- muscle. Force recordings following block of muscle Cl- channels demonstrated little reduction in myotonia in BK-/- muscle. In contrast, the current standard of care, mexiletine, significantly reduced myotonia. Our data suggest BK channels regulate muscle excitability, but are not an attractive target for therapy of myotonia.
    Keywords:  Excitation; K+ channel; Myotonia congenita; Potassium; t-tubule
    DOI:  https://doi.org/10.1007/s00424-024-03005-z
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