Abstract
The marked hypermuscularity in mice with constitutive myostatin deficiency reduces fat accumulation and hyperglycemia induced by high-fat feeding, but it is unclear whether the smaller increase in muscle mass caused by postdevelopmental loss of myostatin activity has beneficial metabolic effects during high-fat feeding. We therefore examined how postdevelopmental myostatin knockout influenced effects of high-fat feeding. Male mice with ubiquitous expression of tamoxifen-inducible Cre recombinase were fed tamoxifen for 2 weeks at 4 months of age. This depleted myostatin in mice with floxed myostatin genes, but not in control mice with normal myostatin genes. Some mice were fed a high-fat diet (60% of energy) for 22 weeks, starting 2 weeks after cessation of tamoxifen feeding. Myostatin depletion increased skeletal muscle mass ∼30%. Hypermuscular mice had ∼50% less weight gain than control mice over the first 8 weeks of high-fat feeding. During the subsequent 3 months of high-fat feeding, additional weight gain was similar in control and myostatin-deficient mice. After 5 months of high-fat feeding, the mass of epididymal and retroperitoneal fat pads was similar in control and myostatin-deficient mice even though myostatin depletion reduced the weight gain attributable to the high-fat diet (mean weight with high-fat diet minus mean weight with low-fat diet: 19.9 g in control mice, 14.1 g in myostatin-deficient mice). Myostatin depletion did not alter fasting blood glucose levels after 3 or 5 months of high-fat feeding, but reduced glucose levels measured 90 min after intraperitoneal glucose injection. Myostatin depletion also attenuated hepatic steatosis and accumulation of fat in muscle tissue. We conclude that blocking myostatin signaling after maturity can attenuate some of the adverse effects of a high-fat diet.
Highlights
When laboratory mice are fed a high-fat diet, they become obese and have hyperglycemia and hepatic steatosis as often observed in obese humans
We used a genetic approach to eliminate myostatin activity after normal development, and we examined how this affected weight gain, muscle mass, fat mass, glucose levels and hepatic steatosis after a prolonged period of high-fat feeding
Beyond 8 weeks, the rate of weight gain was similar in myostatin-deficient and control mice, but cumulative weight gain remained lower in the myostatin-deficient mice
Summary
When laboratory mice are fed a high-fat diet, they become obese and have hyperglycemia and hepatic steatosis as often observed in obese humans. Even on a low-fat diet, mice with constitutive myostatin deficiency are leaner than normal mice [3,4,6,7,8]. Because muscle is a significant glucose consumer when insulin levels are high, and because leanness improves sensitivity to insulin, it is not surprising that constitutive myostatin deficiency reduces hyperglycemia after a glucose challenge in mice with obesity-inducing mutations [6] and in mice fed a high-fat diet [1,3,4]. A constitutive myostatin gene mutation attenuated the hepatic steatosis induced by a high-fat diet [4]
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