IGF1 stimulates greater muscle hypertrophy in the absence of myostatin in male mice

Abstract

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 (<i>Mstn</i>^-/-) mice with mice overexpressing <i>Igf1</i> in skeletal muscle (<i>Igf1</i>⁺) to generate six genotypes of male mice; wild type (<i>Mstn</i><i>^+/+</i> ), <i>Mstn</i>^+/-, <i>Mstn</i>^-/-, <i>Mstn</i><i>^+/+</i><i>:Igf1</i>⁺, <i>Mstn</i>^+/-<i>:Igf1</i>⁺ and <i>Mstn</i>^-/-<i>:Igf1</i>⁺ Overexpression of <i>Igf1</i> increased the mass of mixed fibre type muscles (e.g. <i>Quadriceps femoris</i>) by 19% over <i>Mstn</i><i>^+/+</i> , 33% over <i>Mstn</i>^+/- and 49% over <i>Mstn</i>^-/- (<i>P</i> < 0.001). By contrast, the mass of the gonadal fat pad was correspondingly reduced with the removal of <i>Mstn</i> and addition of <i>Igf1</i> Myostatin regulated the number, while IGF1 regulated the size of myofibres, and the deletion of <i>Mstn</i> and <i>Igf1</i><i>⁺</i> independently increased the proportion of fast type IIB myosin heavy chain isoforms in <i>T. anterior</i> (up to 10% each, <i>P</i> < 0.001). The abundance of AKT and rpS6 was increased in muscles of <i>Mstn</i>^-/-<i>mice</i>, while phosphorylation of AKT^S473 was increased in <i>Igf1</i><i>⁺</i><i>mice</i> (<i>Mstn</i><i>^+/+</i><i>:Igf1</i>⁺, <i>Mstn</i>^+/-<i>:Igf1</i>⁺ and <i>Mstn</i>^-/-<i>:Igf1</i>⁺). 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.