Loss of Ulk1 in skeletal muscle and heart prevents exercise protection against diet‐induced insulin resistance

Abstract

Exercise activates autophagy in both cardiac and skeletal muscle. We have observed that the autophagy protein unc-51 like autophagy activating kinase 1 (Ulk1) is phosphorylated at activating sites during exercise in these tissues. However, the functional role of Ulk1 in the metabolic benefits of exercise remains unknown. We generated heart & muscle-specific Ulk1 knockout (Ulk1 h&mKO) mice by crossing floxed Ulk1 mice with MCK-Cre mice. Ulk1 h&mKO mice had normal exercise capacity and glucose tolerance with a slight (~10%) increase in body weightat 12-14 weeks of age. After 12 weeks on high-fat diet (60% cal. from fat) Ulk1 h&mKO mice did not exhibit major changes in basal autophagy in skeletal muscle or heart and gained weight and developed insulin resistance similarly to their wild-type littermates (WT). Exercise reduced weight gain by ~30% in WT mice, whereas such effect was absent in Ulk1 h&mKO counterparts. Increased glucose intolerance and fasting serum insulin levels were also present in Ulk1 h&mKO mice that exercised despite no differences in food intake or running activity between genotypes. Of note, larger skeletal muscle and heart wet weights, but not adipose tissue depots, were observed in exercise trained Ulk1 h&mKO in relation to WT. These preliminary findings suggest that muscle Ulk1 is required for certain exercise benefits against diet-induced metabolic derangements.