microRNA-1 Regulates Metabolic Flexibility in Skeletal Muscle via Pyruvate Metabolism.

Autor: Ismaeel A; Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.; Center for Muscle Biology, College of Health Sciences, University of Kentucky, Lexington, KY, USA., Peck BD; Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Montgomery MM; Department of Physiology, East Carolina University, Brody School of Medicine, Greenville, NC, USA., Burke BI; Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.; Center for Muscle Biology, College of Health Sciences, University of Kentucky, Lexington, KY, USA., Goh J; Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.; Center for Muscle Biology, College of Health Sciences, University of Kentucky, Lexington, KY, USA., Kang G; Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.; Center for Muscle Biology, College of Health Sciences, University of Kentucky, Lexington, KY, USA.; Division of Biomedical Informatics, Department of Internal Medicine, College of Medicine, University of Kentucky, Lexington, KY, USA., Franco AB; Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.; Mass Spectrometry and Proteomics Core, University of Kentucky, Lexington, KY, USA., Xia Q; Discipline of Physiology, School of Medicine, College of Medicine, Nursing, and Health Sciences, University of Galway, Galway, Ireland., Goljanek-Whysall K; Discipline of Physiology, School of Medicine, College of Medicine, Nursing, and Health Sciences, University of Galway, Galway, Ireland., McDonagh B; Discipline of Physiology, School of Medicine, College of Medicine, Nursing, and Health Sciences, University of Galway, Galway, Ireland., McLendon JM; Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.; Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, United States., Koopmans PJ; Department Health, Human Performance, & Recreation, University of Arkansas, Fayetteville, AR, USA.; Cell and Molecular Biology Graduate Program, University of Arkansas, Fayetteville, AR, USA., Jacko D; Institute of Cardiovascular Research and Sports Medicine, German Sport University, Cologne, Germany.; Olympic Base Center, North Rhine-Westphalia/Rhineland, Cologne, Germany., Schaaf K; Institute of Cardiovascular Research and Sports Medicine, German Sport University, Cologne, Germany.; Olympic Base Center, North Rhine-Westphalia/Rhineland, Cologne, Germany., Bloch W; Institute of Cardiovascular Research and Sports Medicine, German Sport University, Cologne, Germany., Gehlert S; Institute of Cardiovascular Research and Sports Medicine, German Sport University, Cologne, Germany.; Department for the Biosciences of Sports, Institute of Sports Science, University of Hildesheim, Hildesheim, Germany., Wen Y; Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.; Center for Muscle Biology, College of Health Sciences, University of Kentucky, Lexington, KY, USA.; Division of Biomedical Informatics, Department of Internal Medicine, College of Medicine, University of Kentucky, Lexington, KY, USA., Murach KA; Department Health, Human Performance, & Recreation, University of Arkansas, Fayetteville, AR, USA.; Cell and Molecular Biology Graduate Program, University of Arkansas, Fayetteville, AR, USA., Peterson CA; Center for Muscle Biology, College of Health Sciences, University of Kentucky, Lexington, KY, USA., Boudreau RL; Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Fisher-Wellman KH; Department of Physiology, East Carolina University, Brody School of Medicine, Greenville, NC, USA., McCarthy JJ; Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.; Center for Muscle Biology, College of Health Sciences, University of Kentucky, Lexington, KY, USA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2024 Aug 10. Date of Electronic Publication: 2024 Aug 10.
DOI: 10.1101/2024.08.09.607377
Abstrakt: 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.
Databáze: MEDLINE