Abstract 12196: Optic Atrophy 1 Deficiency in Skeletal Muscle Results in Progressive Mitochondrial Dysfunction, but Prevents Age-Induced Obesity and Glucose Intolerance

Abstract

Mitochondrial dysfunction develops in skeletal muscle with aging and may contribute to insulin resistance, which increases cardiovascular risk. A link between skeletal muscle insulin resistance and perturbed mitochondrial fusion and fission has been suggested but not proven. Optic Atrophy 1 (OPA1) is an inner mitochondrial membrane protein that plays a fundamental role in mitochondrial fusion, quality control and respiratory function. OPA1 levels are reduced in muscle from elderly subjects; however, the specific roles of OPA1 in the aging muscle have not been studied. We, therefore, generated a mouse model with inducible deletion of the OPA1 gene in skeletal muscle of adult C57Bl6 mice, by crossing OPA1 floxed mice with HSA-Cre (ERT2) mice (KO). Four-week-old KO and wild-type (WT) mice were treated with tamoxifen for 5 days to induce recombination, resulting in a 60% reduction in OPA1 protein levels 8 weeks after treatment (12-wk-old mice). OPA1 deficiency resulted in altered mitochondrial cristae morphology, with preserved maximally stimulated mitochondria respirations in soleus and reduced ATP synthesis rates in KO mice, 8 weeks after recombination (12-wk-old mice). At 20 weeks, mitochondrial respiration and ATP synthesis were decreased in KO mice, concomitantly with increased AMPK and eIF2 alpha activation. Body weight was reduced in 12 and 20-week old KO mice relative to WT. At forty-weeks, body weight was increased by 40% in WT mice vs. 15% in KO mice. This increase in body weight occurred on the basis of increased fat mass (70% in WT vs. 30% in KO). Lean mass was reduced by 30% in WT mice, which was attenuated in KO mice (~10%). Glucose tolerance tests were similar between WT and KO mice at 12 and 20 weeks of age; however, 40-wk-old WT mice had severe glucose intolerance, which was prevented in KO mice. Interestingly, KO mice had a100-fold increase in FGF21 mRNA levels in muscle compared to WT mice. These data reveal that OPA1 is critical for maintaining skeletal muscle mitochondrial function in the adult muscle and suggest that reducing OPA1 levels activates signaling pathways that retard age-induced obesity and glucose intolerance.