Myostatin Knockout Regulates Bile Acid Metabolism by Promoting Bile Acid Synthesis in Cattle.

Di Wu,Lei Yang,Guanghua Su,Xuefei Liu,Yuefang Zhao,Guangpeng Li,Zhuying Wei,Mingjuan Gu,Chunling Bai

doi:10.3390/ani12020205

Di Wu, Lei Yang + Show 7 more

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https://doi.org/10.3390/ani12020205

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Abstract

Simple SummaryMyostatin (MSTN) gene knockout can increase lean muscle mass and has been widely used in livestock breeding. MSTN deficiency also regulates various metabolic processes. However, the effect of MSTN knockout on the liver, the largest metabolic organ, has not been reported. In this study, physiological and biochemical parameters of serum, untargeted and targeted metabolomics of MSTN+/− and WT cattle were studied, and we found that the knockout of MSTN could regulate liver metabolism and promote bile acid metabolism. This may be due to the enhanced expression of bile acid synthesis genes in MSTN+/− bovine livers. In conclusion, MSTN knockout regulated bile acid metabolism via enhanced bile acid synthesis.Myostatin (MSTN) is a major negative regulator of skeletal muscle mass and causes a variety of metabolic changes. However, the effect of MSTN knockout on bile acid metabolism has rarely been reported. In this study, the physiological and biochemical alterations of serum in MSTN+/− and wild type (WT) cattle were investigated. There were no significant changes in liver and kidney biochemical indexes. However, compared with the WT cattle, lactate dehydrogenase, total bile acid (TBA), cholesterol, and high-density lipoprotein (HDL) in the MSTN+/− cattle were significantly increased, and glucose, low-density lipoprotein (LDL), and triglycerides (TG) were significantly decreased, indicating that MSTN knockout affected glucose and lipid metabolism and total bile acids content. Targeted metabolomic analysis of the bile acids and their derivatives was performed on serum samples and found that bile acids were significantly increased in the MSTN+/− cattle compared with the WT cattle. As the only bile acid synthesis organ in the body, we performed metabolomic analysis on the liver to study the effect of MSTN knockout on hepatic metabolism. Metabolic pathway enrichment analysis of differential metabolites showed significant enrichment of the primary bile acid biosynthesis and bile secretion pathway in the MSTN+/− cattle. Targeted metabolomics data further showed that MSTN knockout significantly increased bile acid content in the liver, which may have resulted from enhanced bile acid synthesis due to the expression of bile acid synthesis genes, cholesterol 7 alpha-hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1), and upregulation in the liver of the MSTN+/− cattle. These results indicate that MSTN knockout does not adversely affect bovine fitness but regulates bile acid metabolism via enhanced bile acid synthesis. This further suggests a role of MSTN in regulating metabolism.

Highlights

Myostatin (MSTN) belongs to the transforming growth factor beta (TGFβ) superfamily
Lipid metabolism test results showed that total bile acid (TBA) (p = 0.00001), cholesterol (p = 0.0011), and high-density lipoprotein (HDL) (p = 0.0014) were significantly increased in the MSTN+/− cattle in comparison with the wild type (WT) cattle
The expression of MSTN was strongly correlated with glucose, HDL, low-density lipoprotein (LDL), TBA, and TG. These results indicated that there were no significant differences in the liver and kidney functions between the MSTN+/− and the WT cattle, while there were significant changes in the serum glucose metabolism, lipid metabolism, and total bile acid levels

Summary

Introduction

Myostatin (MSTN) belongs to the transforming growth factor beta (TGFβ) superfamily. It is the primary negative regulator of skeletal muscle growth and development [1].Inactivation of MSTN by engineered deletion or natural mutation leads to muscle hypertrophy in mice, cattle, humans, sheep, dogs, pigs, and rabbits [2,3,4,5,6,7]. Myostatin (MSTN) belongs to the transforming growth factor beta (TGFβ) superfamily. It is the primary negative regulator of skeletal muscle growth and development [1]. Inactivation of MSTN by engineered deletion or natural mutation leads to muscle hypertrophy in mice, cattle, humans, sheep, dogs, pigs, and rabbits [2,3,4,5,6,7]. MSTN has critical roles in many aspects of metabolism such as glucose and lipid metabolism [8,9]. MSTN inactivation attenuates skeletal muscle insulin resistance and regulates glucose metabolism [8]. It has been reported that MSTN dysfunction decreased the cholesterol of plasma in mice under caloric restriction [13]

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