G.P.196: Metabolic effects of the Compact myostatin

Abstract

The TGF-beta member myostatin is an important negative regulator of skeletal muscle mass, influencing systemic (e.g. carbohydrate) metabolism. Beyond the Smad2/3 mediated signaling events it regulates the PI3K/Akt pathway, which plays a central role in integrating of anabolic and catabolic responses. The Compact ( Cmpt ) mice carry a naturally occurring 12-bp deletion in the propeptide region of the myostatin precursor, and additional modifiers are involved in determining the full expression of the hypermuscular phenotype. The metabolic effects of the Cmpt mutation are poorly understood. According to our results, the absolute weight of the investigated hindlimb muscles and liver significantly increased in Cmpt animals compared to wild-type; however, the muscle weight/body weight ratio significantly increased and the liver weight/body weight ratio significantly decreased in Cmpt s. The total glycogen and protein amount increased in Cmpt M. tibialis anterior, M. quadriceps femoris, M. gastrocnemius and liver samples. Western blot analysis revealed that the mutation resulted in increased level of phospho-Akt (Ser473) in both muscle and liver samples despite the presence of Cmpt myostatin, indicating the absence/reduced effect of myostatin. The glucose tolerance test revealed increased glucose uptake in peripheral tissues of Cmpt s, and the hepatic gluconeogenesis decreased determined by pyruvate tolerance test. To further assess liver function the activity of alanine transaminase (ALT) was measured in vitro, the total liver ALT activity to body mass ratio significantly decreased in Cmpt animals. In conclusion, the Cmpt mutation results in systemic consequences; it has opposite effect on the relative weight and glycogen concentration of skeletal muscle and liver, influences liver function and increases the peripheral glucose uptake.