Myostatin inhibition improves hyperglycemia and hyperphagia in lipodystrophic mice

Background Skeletal muscle is a key peripheral metabolic tissue: Muscle is responsible for most insulin-stimulated glucose uptake, and muscle insulin resistance is the first defect detectable in the development of type 2 diabetes. Recent studies show that muscle mass is inversely correlated with insulin resistance in humans. The growth factor myostatin (MSTN) is a negative regulator of skeletal muscle size. Mstn KO mice or mice expressing a dominant negative activin type receptor type IIB (Acrv2B) specifically in muscle (Muscle-DN mice) have increased muscle mass, reduced adipose mass and improved insulin sensitivity. The improvements in insulin sensitivity could be due to the direct effects of the loss of MSTN in muscle or to the secondary effects of reduced adiposity or both. Our hypothesis is that MSTN inhibition specifically in the muscle can improve hyperglycemia in diabetic mice independent of changes in adiposity. To test this hypothesis, we inhibited MSTN signaling in a diabetic model of generalized lipodystrophy (A-ZIP/F-1 mouse model) to analyze its effects on glucose metabolism separate from effects on adipose mass. The A-ZIP/F-1 fatless mouse is a model of lipodystrophy characterized by the lack of white adipose tissue, diabetes, ectopic lipid accumulation and hyperphagia.