Mighty Mouse: forever fat-free?

According to recent research, Mighty Mouse is unlikely to become obese, and probably has a reduced risk for developing diabetes. In the Journal of Clinical Investigation, McPherron and Lee report that mice with increased muscle mass due to loss of the negative regulator of muscle growth, myostatin (MSTN), also show a reduction in both fat accumulation and abnormal glucose metabolism.

MSTN is a member of the transforming growth factor-β (TGF-β) superfamily of secreted growth and differentiation factors, which have essential roles in regulating tissue development and build-up. MSTN is expressed predominantly in skeletal muscle and at lower levels in adipose tissue, and individual muscles from Mstn -null mice can weigh twice as much as their wild-type counterparts.

Skeletal-muscle function is important for the maintenance of normal glucose function. This, together with the lack of fat in Mstn-null mice, raised the question of whether Mstn might be an effective target for suppressing the development of obesity and diabetes in mouse models of this disease. Mstn-null mice were crossed with two genetic models of obesity — Agouti lethal yellow (A^y) and obese (Lep^ob/ob) mice. Agouti mice become obese because of a dominant mutation that results in antagonism of melanocortin receptors in the hypothalamus, and causes increased food intake. Obese mice have a loss of leptin signalling, which results in severe obesity and abnormalities in glucose metabolism, in part related to the melanocortin-receptor pathways. In both mouse models, loss of Mstn prevents an age-related increase in adipose-tissue mass. The diabetic profiles of the crossed Mstn-null mice were also greatly improved. Agouti mice respond poorly to glucose-tolerance tests; however, glucose and insulin levels after such a test were markedly lower in Mstn-null Agouti mice. In addition, the usual development of hyperglycaemia in obese mice was significantly delayed in the Mstn-null obese mice. Pharmacological agents that block MSTN function could be useful for slowing or preventing the development of obesity and type 2 diabetes.

Clearly, deletion of Mstn affects adipose-tissue mass as well as skeletal mass, although it is unclear whether the effect on adipose tissue is direct or indirect. If MSTN has the same role in humans as in mice, in addition to its potential utility as a drug target in obesity and diabetes, it could also be a target for increasing skeletal-muscle mass in patients with muscle-wasting diseases.