IGF1 does not overcome sexual dimorphism of body and muscle size in Mstn−/− mice

Abstract

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.

The minor allele of the CREBRF rs373863828 p.R457Q coding variant is associated with reduced levels of myostatin in males: Implications for body composition

“…A allele with reduction in myostatin levels in both the mice and in the human participants in our study. This is likely to contribute to the increase in relative lean mass as lower myostatin is associated with increased in muscle mass [23,31] and reductions in fat [26]. It is known that lower levels of myostatin result in increases in relative lean mass with ageing which is consistent with our findings [32].…”

“…Given that it is known there is sexual dimorphism in the regulation of myostatin [25,31,46] it is possible that different effects will be observed in women. Other sexually dimorphic effects of rs373863828 have been observed, for example the male-specific effects observed on height [17,47] and differences in the pattern of body composition between males and females [15].…”

The minor allele of the CREBRF rs373863828 p.R457Q coding variant is associated with reduced levels of myostatin in males: Implications for body composition

“…An important finding of the current study is the association of the rs373863828 A allele with reduction in myostatin levels in both the mice and the human participants. This is likely to contribute to differences in body composition as lower myostatin is associated with increased muscle mass [ 23 , 32 ] and reductions in fat mass [ 26 ]. It is known that lower levels of myostatin result in changes in body composition with ageing, and this is consistent with our findings [ 33 ].…”

“…One limitation of our study is that our human cohort did not include females. Given that it is known there exists sexual dimorphism in the regulation of myostatin [ 25 , 32 , 41 ], it is possible that different effects will be observed in women. Other sexually dimorphic effects of rs373863828 have been observed, for example, the male-specific effects observed on height [ 17 , 42 ] and differences in the pattern of body composition between males and females [ 15 , 43 ].…”