Effect of Myostatin Depletion on Weight Gain, Hyperglycemia, and Hepatic Steatosis during Five Months of High-Fat Feeding in Mice

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.

AAV-Mediated Administration of Myostatin Pro-Peptide Mutant in Adult Ldlr Null Mice Reduces Diet-Induced Hepatosteatosis and Arteriosclerosis

“…D76A-treated mice showed a small decrease in inguinal fat but fat mass in perirenal, epididymal, and mesenteric depots were not different between the two groups (Figure S2C). This is in striking contrast to the global hypoadiposity found in mice with life-long genetic myostatin blockade [1]–[5], [18], but in line with a recent study on diet-induced metabolic disorders in mice with adult age myostatin deletion [19].…”

“…Indeed, it has been shown that life-long muscle-specific transgenic myostatin blockade was sufficient to reproduce the phenotype of mice with global myostatin knockout, unequivocally proving that dramatic muscle hypertrophy alone is sufficient to cause global metabolic protections [1], [3], [18]. However, such extremely hypertrophic muscle phenotype was not reproduced in mice with adult age myostatin inhibition [6]–[9], [19], [47](this work). In addition, life-long genetic myostatin blockade, global or muscle-specific, prevents diet-induced increment in fat mass [1]–[3], [5], a phenotype that was also not reproducible in mice with adult age myostatin inhibition ([19], this work).…”

“…In addition, life-long genetic myostatin blockade, global or muscle-specific, prevents diet-induced increment in fat mass [1]–[3], [5], a phenotype that was also not reproducible in mice with adult age myostatin inhibition ([19], this work). However, despite a modest impact on body composition, adult age myostatin inhibition does prove effective in protection against diet-induced fatty liver ([19], this work) and atherosclerosis (this work), thus prompting us to consider organ-specific effect of myostatin (and its inhibitors) on metabolic regulations without being overwhelmed by the hyper-muscular phenotype found in mice with life-long genetic myostatin blockade.…”

High-fat diet reduces local myostatin-1 paralog expression and alters skeletal muscle lipid content in rainbow trout, Oncorhynchus mykiss

“…While most research investigating the role(s) of myostatin have focused on its regulation of skeletal muscle mass, an accumulating amount of evidence suggests that this protein may play a pivotal role in energy partitioning, particularly by promoting adiposity (Zhang et al 2012; Burgess et al 2011; Lyons et al 2010; Guo et al 2009; Hamrick et al 2006; Zhao et al 2005). These studies have convincingly demonstrated that knockdown, inhibition, or deletion of myostatin promotes ‘normal’ body lean mass under high fat dietary insult.…”

Myostatin mediates abdominal aortic atherosclerosis progression by inducing vascular smooth muscle cell dysfunction and monocyte recruitment

“…Moreover, the exposure of aortic endothelial cells to Mstn leads to activation of TGF-β signaling, decrease of the endothelial NO synthase (eNOS) phosphorylation and increased expression of pro-atherogenic adhesion molecules ICAM-1 and VCAM-123. These findings suggest that the components of vessel wall are direct targets of Mstn, and that therefore Mstn may be relevant for diet-induced metabolic disorders25.…”