Location: Children's Nutrition Research CenterTitle: IGF1 stimulates greater muscle hypertrophy in the absence of myostatin in male mice
|HENNEBRY, ALEXANDER - Agresearch|
|OLDHAM, JENNY - Agresearch|
|SHAVLAKADZE, TEA - University Of Western Australia|
|GROUNDS, MIRANDA - University Of Western Australia|
|SHEARD, PHILIP - University Of Otago|
|FIOROTTO, MARTA - Children'S Nutrition Research Center (CNRC)|
|FALCONER, SHELLEY - Agresearch|
|SMITH, HEATHER - University Of Auckland|
|BERRY, CAROLE - Agresearch|
|JEANPLONG, FERENC - Agresearch|
|BRACEGIRDLE, JEREMY - Agresearch|
|MATTHEWS, KENNETH - Agresearch|
|NICHOLAS, GINA - Agresearch|
|SENNA-SALERNO, MONICA - Agresearch|
|WATSON, TREVOR - Agresearch|
|MCMAHON, CHRISTOPHER - Agresearch|
Submitted to: Journal of Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/22/2017
Publication Date: 5/22/2017
Citation: Hennebry, A., Oldham, J.M., Shavlakadze, T., Grounds, M., Sheard, P., Fiorotto, M., Falconer, S.J., Smith, H.K., Berry, C., Jeanplong, F., Bracegirdle, J., Matthews, K.G., Nicholas, G., Senna-Salerno, M., Watson, T., McMahon, C.D. 2017. IGF1 stimulates greater muscle hypertrophy in the absence of myostatin in male mice. Journal of Endocrinology. doi:10.1530/JOE-17-0032.
Interpretive Summary: Skeletal muscle makes the largest contribution to the growth of the newborn and is strongly dependent on the consumption of adequate protein from the diet. Two unique properties of skeletal muscle when it is immature are that it expresses high levels of a growth factor called IGF1 and very low levels of an inhibitor of muscle growth called myostatin. As muscles mature and their growth diminishes, IGF1 decreases and myostatin increases. In this study we wanted to establish if these molecules had opposite effects on the same mechanism, or if they work through different mechanisms. To do this we used genetic mouse models in which these factors were individually altered (myostatin was removed, or IGF1 was added back, or both changes together) and compared their muscles to normal mice. We showed that the individual changes stimulated muscle growth and a decrease in fat, but the response was greater than additive when both were changed together. These responses occurred because myostatin and IGF1 use different mechanisms to alter muscle growth. Understanding how nutrients affect the levels of both of these factors in early life may help us better determine the optimum nutrient mix to promote muscle growth.
Technical 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 (Mstn-/-) mice with mice over-expressing Igf1 in skeletal muscle (Igf1+) to generate six genotypes of male mice; wild-type (Mstn+/+), Mstn+/-, Mstn-/-, Mstn+/+:Igf1+, Mstn+/-:Igf1+ and Mstn-/-:Igf1+. Over-expression of Igf1 increased the mass of mixed fiber 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 removal of Mstn and addition of Igf1. Myostatin regulated the number, while IGF1 regulated the size of myofibres, and 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 were 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.