Loss-of-function myostatin mutation increases insulin sensitivity and browning of white fat in Meishan pigs.

Chunbo Cai,Shengwang Jiang,Dezun Ma,Youde Sun,Wentao Cui,Jie Liu,Ting Gao,Lili Qian,Yaoxing Chen,Xiaorong An,Gaojun Xiao,Kui Li,Qingqing Wang,Biao Li,Shanshan Xie

doi:10.18632/oncotarget.16822

Abstract

Myostatin-deficient mice showed a remarkable hypertrophy of skeletal muscle, with a decreased fat mass and enhanced insulin sensitivity. Currently, it is unclear if the inhibition of myostatin could be used as an approach to treat human obesity and insulin resistance. In this study, we investigated if the inhibition of porcine myostatin has any effect on fat deposition and insulin sensitivity using genetically engineered Meishan pigs containing a myostatin loss-of-function mutation (Mstn −/− ). Our results indicated that, when compared with wild-type pigs, the amount of subcutaneous fat and leaf fat of Mstn −/− pigs were significantly decreased mainly due to the browning of subcutaneous adipose tissue. Additionally, the serum insulin level decreased and the insulin sensitivity increased significantly in Mstn −/− pigs. Moreover, we found a significant increase in levels of insulin receptor and insulin receptor substrate proteins in skeletal muscle of Mstn −/− pigs, which then activating the insulin signaling pathway. Irisin-mediated regulation is not the only pathway for the activation of insulin signal in Mstn −/− skeletal muscle. This study provides valuable insight for the treatment of human obesity and diabetes mellitus.

Highlights

Myostatin is a transcriptional growth factor, known as growth/differentiation factor 8 (GDF8), which is a member of the transforming growth factor beta (TGFβ) superfamily
We investigated if the inhibition of porcine myostatin has any effect on fat deposition and insulin sensitivity using genetically engineered Meishan pigs containing a myostatin loss-of-function mutation (Mstn −/− )
The effect of myostatin deficiency on skeletal muscle and fat was further investigated at ages of 4 months and 16 months, respectively

Summary

Introduction

Myostatin is a transcriptional growth factor, known as growth/differentiation factor 8 (GDF8), which is a member of the transforming growth factor beta (TGFβ) superfamily. Myostatin is expressed mainly in skeletal muscle [1], and a small amount can be detected in fat, brain, heart, liver, and kidney [2, 3]. The main function of myostatin is its negative regulation of skeletal muscle growth and development [4]. Mstn −/− mice have a remarkable increase in skeletal muscle mass and a significant decrease in fat mass when compared with their corresponding wild-type littermates [1]. It has been well established that natural mutations in myostatin can lead to skeletal muscle hypertrophy in species such as cattle [5, 6]. Myostatin becomes an important target for improving lean meat production in livestock production

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Conclusion