SUN-LB118 Mice With Skeletal Muscle-Specific DRP1 Deficiency Are Resistant to Obesity and Diabetes Induced by a High Fat Diet

Abstract

The skeletal muscle of type 2 diabetics exhibits mitochondrial dysfunction associated with increased mitochondrial fission. Dynamin-related protein 1 (DRP1) is responsible for mitochondrial division, whereas mitochondrial-endoplasmic reticulum contacts (MERCs) mark mitochondrial sites where fission occurs. Here, we have shown that skeletal muscle-specific DRP1 knock out (KO) mice are partly protected from high fat diet-induced obesity and diabetes, and exhibit increased insulin and glucose tolerance along with lower insulinemia. We also found that KO mice exhibit increased energy expenditure per unit of lean mass. Isolated DRP1-deficient skeletal muscle fibers from KO mice fed high fat diet have reduced respiratory capacity when exposed to ADP and palmitoyl-carnitine, but not when exposed to ADP, pyruvate, and malate. Additionally, the skeletal muscle of KO mice fed normal chow exhibited altered expression of genes associated with MERCs and increased expression of genes linked to ER stress. We observed substantial increases in gene expression of FGF21, a downstream signal of the ER stress response, in KO mice. However, FGF21 plasma concentration in KO mice was not elevated. Additionally, changes in MERC gene expression could potentially alter calcium signaling between the mitochondria and endoplasmic reticulum, changing insulin sensitivity in KO mice. In conclusion, we have shown that skeletal muscle-specific DRP1 KO mice are resistant to high fat diet-induced obesity and diabetes, perhaps due to elevated energy expenditure and differential mitochondrial respiratory adaptations to different substrates. Although FGF21 does not appear to contribute to this effect, it is possible that other ER-stress signals might help explain the observed phenotype in KO mice.

A Comprehensive Approach to Sample Preparation for Electron Microscopy and the Assessment of Mitochondrial Morphology in Tissue and Cultured Cells

“…However, similar to the Mfn2 , Opa1 deletion resulted in increased percent of MERCs coverage of both the ER and mitochondria relative to control myotubes ( Figure 3L , M ). We further performed MERCs quantification in Drp1 -deficient murine myotubes [ 66 ] ( Figure S2 , Supporting Information ). Similar to Mfn2 deletion, there was an increase in MERCs distance and ER surface area ( Figure S2E , F , Supporting Information ).…”