Myostatin Inhibits Fatty-Acid Oxidation and Glucose Uptake in Myoblasts and Suppresses Adiponectin Biosynthsis By Adipocytes

Presentation Number: SUN 248
Date of Presentation: April 2nd, 2017

Xin-Hua Liu*1, William A Bauman2 and Christopher Pratt Cardozo3
1J.J. Peter VA Medical Center, Bronx, NY, 2James J. Peters VA Medical Center, Bronx, NY, 3J.J.Peter Veteran Affairs Medical Center, Bronx, NY


Myostatin (MSTN) is a myokine and has been recognized for its ability to regulate overall body composition. While the beneficial effects of MSTN inhibition on muscle mass are well known, its role on lipid and glucose metabolism and energy expenditure in muscle and adipose tissue are not as well delineated. In addition, the specific mechanisms and signaling events related to crosstalk between skeletal muscle and adipose tissues are not fully understood. Moreover, whether MSTN directly regulates adipose tissue mass, as it does in skeletal muscle, is unclear. With these considerations in mind, we initially examined the effect of MSTN on activation of AMP-activated protein kinase (AMPK), a cellular sensor of energy homeostasis, in myoblasts (C2C12) and adipocytes (3T3L1). Cells were incubated in differentiating medium (2% horse serum) for 4d and treated with MSTN for an additional 3d, a significant inhibition in phosphorylation of AMPK (Thr172) was observed in both C2C12 (50%, p<0.01) and 3T3L1 (40%, p<0.01) cells. MSTN also suppressed the expression of PGC1α mRNA and protein in both C2C12 and 3T3L1 cells, which is a key regulator of mitochondrial biogenesis. To elucidate downstream consequences of AMPK inhibition by MSTN, the effects of MSTN on fatty acid oxidation and glucose uptake in differentiated C2C12 and 3T3L1 cells were examined. Treatment of C2C12 cells with MSTN for 3d significantly inhibited phosphorylation (Ser79) of acetyl-coenzyme A carboxylase (ACC) (55%, p<0.01), suggesting an inhibition of fatty acid oxidation. MSTN treatment also inhibited GLUT4 mRNA and protein expression. The reduction in GLUT4 expression was associated with a reduced rate of glucose uptake in MSTN-treated C2C12 cells compared to that of vehicle-treated C2C12 cells (50%, p<0.01). In contrast, MSTN treatment had no effect on ACC phosphorylation, GLUT4 expression or glucose uptake in 3T3L1 cells. Adiponectin, an adipocyte-derived hormone, has been shown to activate AMPK. The effect of MSTN on adiponectin biosynthesis and secretion by 3T3L1 cells was tested next. Rt-PCR demonstrated a significant decrease in adiponectin mRNA expression in the cells treated with MSTN for 2d. Western blot analysis on the medium derived from cultured adipocytes showed reduced secretion of adiponectin in MSTN-treated cells. The MSTN-induced inhibition of adiponectin secretion by 3T3L1 cells was confirmed by ELISA (55%, p<0.05). These data indicated that MSTN has distinct effects on cell metabolism in muscle and adipose cells via inhibition of AMPK activation. Based on the fact that adiponectin receptor-1 is abundantly expressed in skeletal muscle (1), our findings implicate a crosstalk between muscle and adipose cells by which skeletal muscle energy metabolism is regulated, and suggest that this interaction is mediated, at least in part, by MSTN and adiponectin.


Nothing to Disclose: XHL, WAB, CPC