Skeletal muscle of type 2 diabetic patients exhibit mitochondrial dysfunction associated with increased mitochondrial fragmentation. Dynamin-related protein 1 (DRP1) is responsible for mitochondrial membrane constriction during mitochondrial fission whereas mitochondrial-endoplasmic reticulum contacts (MERCs) mark mitochondrial sites of this process. We tested the hypothesis that DRP1 deficiency in skeletal muscle alters mRNA expression of proteins involved in MERCs and endoplasmic reticulum stress (ERS).


We developed a model of inducible DRP1 deficiency in skeletal muscle by crossing mice with DRP1 floxed alleles with mice harboring HAS/ERT2-CRE recombinase.


DRP1 mRNA and protein expression were respectively reduced by 60% and 40% in skeletal muscle of homozygous floxed mice expressing CRE [knock out (KO) mice].The KO mice were resistant to weight and fat mass gain during 60% high fat diet, which was associated with improved tolerance to glucose and increased energy expenditure. We studied MERCs and ERS in normal chow diet-fed KO and wild type (WT) mice. The mRNA expression of GRP75 was increased while VDAC1 was decreased suggesting altered MERCs in KO mice. The mRNA expression of BIP, CHOP, IRE1 and, notably, FGF21 were increased in KO mice indicating activation of ERS.


Our study suggests that myokines secreted during ERS, such as FGF21, might help explain the metabolic benefit of DRP1 deficiency in skeletal muscle. Alternatively, altered MERCs can potentially change calcium transients between mitochondria and the endoplasmic reticulum and modify insulin sensitivity in mice deficient of DRP1 in skeletal muscle.