Premium
Myostatin blockade with a form of the ActRIIB receptor has potent anti‐obesity and insulin sensitizing actions
Author(s) -
Akpan Imo,
Dhir Ravindra,
Yin Xiaoyan,
Lachey Jennifer,
Goncalves Marcus,
Ahima Rexford S
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.990.4
Subject(s) - myostatin , medicine , endocrinology , skeletal muscle , glucose homeostasis , insulin , receptor , blockade , activin receptor , insulin receptor , carbohydrate metabolism , glucose uptake , insulin resistance , biology
Myostatin (GDF‐8), a member of the Growth and Differentiation Factor (GDF) family, inhibits muscle growth. The cellular action of myostatin is mediated by the activin receptor type IIB (ActRIIB). Loss‐of‐function mutations of the myostatin gene or disruption of myostatin signaling increases muscle mass. Skeletal muscle is the major organ for glucose disposal, thus we hypothesized that blockade of myostatin would enhance glucose metabolism. We administered a decoy form of the activin type IIB receptor [RAP‐031 10 mg/kg] or vehicle intraperitoneally twice weekly for 10 weeks in C57BL/6J mice. RAP‐031 increased body weight and lean tissue and decreased fat content in mice fed regular chow or high‐fat (45%) diet. RAP‐031 increased the weights of soleus, gastrocnemius and tibialis anterior muscles, as well muscle fiber diameters. We assessed glucose homeostasis using hyperinsulinemic‐euglycemic clamp and radioisotopic tracer kinetics. RAP‐031 increased the glucose infusion and disposal rates by 119% and 45% respectively, and suppressed hepatic glucose production by 66%. Together, these results demonstrate that blockade of myostatin signaling by treatment with an ActRIIB‐based therapeutic is a viable approach toward increasing muscle mass, decreasing fat and improving insulin sensitivity. [ This work was supported by National Institutes of Health grant R01DK062348 and an Acceleron Pharma research gift].