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Ryan G Paul, Kim Whiteman, Shelley J Falconer, Jenny Oldham, Ferenc Jeanplong, Kenneth G Matthews, Heather K Smith, Mark Thomas, Trevor Watson, and Christopher D McMahon

Insulin-like growth factor-1 (IGF1) is crucial for regulating post-natal growth and, along with myostatin, regulates muscle size. Here, we sought to clarify the roles of these two genes in regulating sexually dimorphic growth of body and muscle mass. In the first study, we established that Igf1 mRNA was increased to a greater extent and Igf1 receptor mRNA increased earlier in male, than in female, gastrocnemius muscles during the rapid phase of growth (2 to 6 weeks), but were unchanged, thereafter, to 32 weeks of age in wild-type mice (P<0.001). In the second study, we sought to determine if supplemental IGF1 could overcome the sexual dimorphism of muscle and body mass, when myostatin is absent. We crossed myostatin null (Mstn-/-) mice with mice over-expressing Igf1 in skeletal muscle (Igf1+) to generate six genotypes; control (Mstn+/+), Mstn+/-, Mstn-/-, Mstn+/+:Igf1+, Mstn+/-:Igf1+ and Mstn-/-:Igf1+ (n=8 per genotype and sex). In both sexes, body mass at 12 weeks was increased by at least 1.6-fold and muscle mass by at least 3-fold in Mstn-/-:Igf1+ compared with Mstn+/+ mice (P<0.001). The abundance of Akt was increased in muscles of mice transgenic for Mstn, while phosphorylation of AktS473 was increased in both male and female mice transgenic for Igf1+. The ratio of phosphorylated to total Akt was 1.9-fold greater in male mice (P<0.001). Thus, despite increased growth of skeletal muscle and body size when myostatin was absent and IGF1 was in excess, sexual dimorphism persisted, an effect consistent with greater IGF1-induced activation of Akt in skeletal muscles of males.

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Alexander Hennebry, Jenny Oldham, Tea Shavlakadze, Miranda D Grounds, Philip Sheard, Marta L Fiorotto, Shelley Falconer, Heather K Smith, Carole Berry, Ferenc Jeanplong, Jeremy Bracegirdle, Kenneth Matthews, Gina Nicholas, Mônica Senna-Salerno, Trevor Watson, and Christopher D McMahon

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 AKTS473 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.