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CDK4-E2F3 signals enhance oxidative skeletal muscle fiber numbers and function to affect myogenesis and metabolism.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2023 Jul 03; Vol. 133 (13). Date of Electronic Publication: 2023 Jul 03. - Publication Year :
- 2023
-
Abstract
- Understanding how skeletal muscle fiber proportions are regulated is vital to understanding muscle function. Oxidative and glycolytic skeletal muscle fibers differ in their contractile ability, mitochondrial activity, and metabolic properties. Fiber-type proportions vary in normal physiology and disease states, although the underlying mechanisms are unclear. In human skeletal muscle, we observed that markers of oxidative fibers and mitochondria correlated positively with expression levels of PPARGC1A and CDK4 and negatively with expression levels of CDKN2A, a locus significantly associated with type 2 diabetes. Mice expressing a constitutively active Cdk4 that cannot bind its inhibitor p16INK4a, a product of the CDKN2A locus, were protected from obesity and diabetes. Their muscles exhibited increased oxidative fibers, improved mitochondrial properties, and enhanced glucose uptake. In contrast, loss of Cdk4 or skeletal muscle-specific deletion of Cdk4's target, E2F3, depleted oxidative myofibers, deteriorated mitochondrial function, and reduced exercise capacity, while increasing diabetes susceptibility. E2F3 activated the mitochondrial sensor PPARGC1A in a Cdk4-dependent manner. CDK4, E2F3, and PPARGC1A levels correlated positively with exercise and fitness and negatively with adiposity, insulin resistance, and lipid accumulation in human and rodent muscle. All together, these findings provide mechanistic insight into regulation of skeletal muscle fiber-specification that is of relevance to metabolic and muscular diseases.
- Subjects :
- Mice
Animals
Humans
Muscle Fibers, Skeletal metabolism
Muscle Fibers, Slow-Twitch metabolism
Muscle, Skeletal metabolism
Obesity metabolism
Oxidative Stress
Muscle Development
E2F3 Transcription Factor metabolism
Cyclin-Dependent Kinase 4 genetics
Cyclin-Dependent Kinase 4 metabolism
Diabetes Mellitus, Type 2 genetics
Diabetes Mellitus, Type 2 metabolism
Muscular Diseases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 133
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 37395281
- Full Text :
- https://doi.org/10.1172/JCI162479