Insulin-like growth factors (IGFs) and myostatin have opposing roles in regulating the growth and size of skeletal muscle, with IGF1 stimulating, and myostatin inhibiting, growth. However, it remains unclear whether these proteins have mutually dependent, or independent, roles. To clarify this issue, we crossed myostatin null (Mstn^-/-) mice with mice overexpressing Igf1 in skeletal muscle (Igf1⁺) to generate six genotypes of male mice; wild type (Mstn^+/+ ), Mstn^+/-, Mstn^-/-, Mstn^+/+:Igf1⁺, Mstn^+/-:Igf1⁺ and Mstn^-/-:Igf1⁺ Overexpression of Igf1 increased the mass of mixed fibre type muscles (e.g. Quadriceps femoris) by 19% over Mstn^+/+ , 33% over Mstn^+/- and 49% over Mstn^-/- (P < 0.001). By contrast, the mass of the gonadal fat pad was correspondingly reduced with the removal of Mstn and addition of Igf1 Myostatin regulated the number, while IGF1 regulated the size of myofibres, and the deletion of Mstn and Igf1⁺ independently increased the proportion of fast type IIB myosin heavy chain isoforms in T. anterior (up to 10% each, P < 0.001). The abundance of AKT and rpS6 was increased in muscles of Mstn^-/-mice, while phosphorylation of AKT^S473 was increased in Igf1⁺mice (Mstn^+/+:Igf1⁺, Mstn^+/-:Igf1⁺ and Mstn^-/-:Igf1⁺). Our results demonstrate that a greater than additive effect is observed on the growth of skeletal muscle and in the reduction of body fat when myostatin is absent and IGF1 is in excess. Finally, we show that myostatin and IGF1 regulate skeletal muscle size, myofibre type and gonadal fat through distinct mechanisms that involve increasing the total abundance and phosphorylation status of AKT and rpS6.

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