Pluto Bioinformatics

GSE103722: Skeletal muscle ERalpha action is critical for the maintenance of mitochondrial dynamics and metabolic homeostasis in male mice

Bulk RNA sequencing

Impaired estrogen production and action are associated with obesity and insulin resistance in male males however the tissues critical for estrogen action in the maintenance of metabolic homeostasis remain inadequately understood. Moreover, the cell specific target genes and molecular actions of estrogen in males remain unknown. We generated male mice with a muscle-specific ERa knockout (MERKO) to determine the role of this hormone nuclear receptor in controlling metabolic function and insulin action in skeletal muscle. Male MERKO mice became insulin resistant with age and accumulated more adipose tissue than floxed control mice. Skeletal muscle was distinguished by enlarged hyper-fused mitochondria that produced increased amounts of superoxide, and this was associated with enhanced proinflammatory signaling. The striking mitochondrial phenotype was accompanied by reduced protein abundance of electron transport chain proteins and the mitochondrial biogenesis marker Pgc1a. Muscle from MERKO mice showed imbalanced protein abundance of mitochondrial fission-fusion proteins most notably marked reductions in total DRP1, MFN1, and OPA1 were observed compared with f/f control. To recapitulate the reduction in DRP1 protein leading to impairment in mitochondrial fission, we generated mice with a muscle-specific heterozygous deletion in Drp1 (mDrp1+/-). mDrp1+/- mice phenocopied the aberrant muscle mitochondrial morphology and dysfunction of the MERKO mice and developed insulin resistance with age. Skeletal muscle ERa is critical for the maintenance of mitochondrial function and metabolic homeostasis in male mice. SOURCE: Calvin Pan UCLA