Abstract
Genetic disruption of myostatin or its related signaling is known to cause strong protection against diet-induced metabolic disorders. The translational value of these prior findings, however, is dependent on whether such metabolically favorable phenotype can be reproduced when myostatin blockade begins at an adult age. Here, we reported that AAV-mediated delivery of a myostatin pro-peptide D76A mutant in adult mice attenuates the development of hepatic steatosis and arteriosclerosis, two common diet-induced metabolic diseases. A single dose of AAV-D76A in adult Ldlr null mice resulted in sustained expression of myostatin pro-peptide in the liver. Compared to vehicle-treated mice, D76A-treated mice gained similar amount of lean and fat mass when fed a high fat diet. However, D76A-treated mice displayed significantly reduced aortic lesions and liver fat, in association with a reduction in hepatic expression of lipogenic genes and improvement in liver insulin sensitivity. This suggests that muscle and fat may not be the primary targets of treatment under our experimental condition. In support to this argument, we show that myostatin directly up-regulated lipogenic genes and increased fat accumulation in cultured liver cells. We also show that both myostatin and its receptor were abundantly expressed in mouse aorta. Cultured aortic endothelial cells responded to myostatin with a reduction in eNOS phosphorylation and an increase in ICAM-1 and VCAM-1 expression. Conclusions: AAV-mediated expression of myostatin pro-peptide D76A mutant in adult Ldlr null mice sustained metabolic protection without remarkable impacts on body lean and fat mass. Further investigations are needed to determine whether direct impact of myostatin on liver and aortic endothelium may contribute to the related metabolic phenotypes.
Highlights
Metabolic disorders, such as diabetes mellitus, nonalcoholic fatty liver disease, and arteriosclerosis are leading causes of morbidity and mortality in modern world
Effects of D76A on Body Composition Consistent with previous reports [7], we observed a modest increase in lean body mass in mice following the injection of AAVD76A while the mice were maintained on a low fat chow (Figure S2A)
During the period of high fat diet, the changes in lean and fat mass were similar between the vehicle and D76A-treated animals (Figure S2B)
Summary
Metabolic disorders, such as diabetes mellitus, nonalcoholic fatty liver disease, and arteriosclerosis are leading causes of morbidity and mortality in modern world. With the aging of human populations, the prevalence of these inter-linked metabolic disorders is increasing globally. We show here that myostatin, a muscle-secreted growth and differentiation factor, may be a potential therapeutic target for the prevention and treatment of these metabolic disorders. Genetic inactivation of myostatin in Ldlr null mice alleviates dietinduced hepatosteatosis and arteriosclerosis [5]. It is not known whether similar metabolic improvement can be achieved by myostatin antagonists in adults, an issue that is crucially important for the relevant clinical applications
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