Suppression of body fat accumulation in myostatin-deficient mice

Abstract

Myostatin is a TGF-beta family member that acts as a negative regulator of muscle growth. Mice lacking the myostatin gene (Mstn) have a widespread increase in skeletal muscle mass resulting from a combination of muscle fiber hypertrophy and hyperplasia. Here we show that Mstn-null mice have a significant reduction in fat accumulation with increasing age compared with wild-type littermates, even in the setting of normal food intake (relative to body weight), normal body temperature, and a slightly decreased resting metabolic rate. To investigate whether myostatin might be an effective target for suppressing the development of obesity in settings of abnormal fat accumulation, we analyzed the effect of the Mstn mutation in two genetic models of obesity, agouti lethal yellow (A(y)) and obese (Lep(ob/ob)). In each case, loss of Mstn led to a partial suppression of fat accumulation and of abnormal glucose metabolism. Our findings raise the possibility that pharmacological agents that block myostatin function may be useful not only for enhancing muscle growth, but also for slowing or preventing the development of obesity and type 2 diabetes.

Figure 1

Mstn deletion suppresses fat accumulation. (a) Increased mass of triceps muscle in Mstn^–/– mice at different ages (n = 4–13). Black, Mstn^+/+; blue, Mstn^+/–; pink, Mstn^–/–. Data are expressed as mean ± SEM. (b–f) Mass of male epididymal (b), retroperitoneal (c), and inguinal (d), and female parametrial (e) and retroperitoneal (f) fat pads at different ages (n = 4–13). Orange bars designate the mean, and symbols designate individual animals colored as in a, with diamonds for males and circles for females. ^#P = 0.05, *P < 0.05, **P < 0.01, ***P < 0.001, Student’s t test. (g) Serum concentration of leptin to mass of total body fat in individual 8-month-old male mice. (h) Fat cell histology in epididymal fat pads. Scale bar = 50 μm.

Figure 2

Expression of uncoupling proteins. Fifteen micrograms of total RNA isolated from various tissues in Mstn^+/+ and Mstn^–/– mice was electrophoresed, blotted, and probed with Ucp1, Ucp2, and Ucp3. Each blot was also hybridized with an S26 ribosomal protein probe as a loading control.

Figure 3

Mstn deletion partially suppresses fat accumulation and glucose intolerance in A^y mice. (a) Effect of Mstn deletion on appearance of a/a and A^y/a female mice. (b and c) Effects of Mstn deletion on fat pad weights in 7-month-old A^y male (b) (n = 6–9) and female (c) (n = 8–20) mice. Orange bars designate the mean, and symbols designate individual animals. Black, A^y/a, Mstn^+/+; pink, A^y/a, Mstn^–/–. Diamonds, males; circles, females. (d and e) Suppression of abnormality of glucose tolerance tests in male (d) (n = 4) and female (e) (n = 5–13) Mstn^–/– mice. Symbols are as in b and c. Some measurements exceeded the upper detection limit of the glucose test (600 mg/dl). *P < 0.05, ***P < 0.001, Student’s t test.

Figure 4

Mstn deletion partially suppresses fat accumulation and delays hyperglycemia in Lep^ob/ob mice. (a and b) Decrease in fat pad weights in male (a) (n = 5–8) and female (b) (n = 5–6) Lep^ob/ob, Mstn^–/– 8-week-old mice. Orange bars designate the mean, and symbols designate individual animals. Black, Lep^ob/ob, Mstn^+/+; pink, Lep^ob/ob, Mstn^–/–. Diamonds, males; circles, females. (c and d) Suppression of abnormal fed glucose levels in Lep^ob/ob, Mstn^–/– male (c) (n = 6–22) and female (d) (n = 8–26) mice. Symbols are as in a and b. *P < 0.05, **P < 0.01, ***P < 0.001, Student’s t test.