TY - JOUR
T1 - microRNA-1 Regulates Metabolic Flexibility in Skeletal Muscle via Pyruvate Metabolism
AU - Ismaeel, Ahmed
AU - Peck, Bailey D
AU - Montgomery, McLane M
AU - Burke, Benjamin I
AU - Goh, Jensen
AU - Kang, Gyumin
AU - Franco, Abigail B
AU - Xia, Qin
AU - Goljanek-Whysall, Katarzyna
AU - McDonagh, Brian
AU - McLendon, Jared M
AU - Koopmans, Pieter J
AU - Jacko, Daniel
AU - Schaaf, Kirill
AU - Bloch, Wilhelm
AU - Gehlert, Sebastian
AU - Wen, Yuan
AU - Murach, Kevin A
AU - Peterson, Charlotte A
AU - Boudreau, Ryan L
AU - Fisher-Wellman, Kelsey H
AU - McCarthy, John J
PY - 2024/8/10
Y1 - 2024/8/10
N2 - 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.
AB - 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.
U2 - 10.1101/2024.08.09.607377
DO - 10.1101/2024.08.09.607377
M3 - Article
C2 - 39149347
SN - 2692-8205
JO - bioRxiv : the preprint server for biology
JF - bioRxiv : the preprint server for biology
ER -