Establishment and phenotypic analysis of an Mstn knockout rat

Abstract

Myostatin (Mstn) is an inhibitor of myogenesis, regulating the number and size of skeletal myocytes. In addition to its myogenic regulatory function, Mstn plays important roles in the development of adipose tissues and in metabolism. In the present study, an Mstn knockout rat model was generated using the zinc finger nuclease (ZFN) technique in order to further investigate the function and mechanism of Mstn in metabolism. The knockout possesses a frame shift mutation resulting in an early termination codon and a truncated peptide of 109 amino acids rather than the full 376 amino acids. The absence of detectable mRNA confirmed successful knockout of Mstn. Relative to wild-type (WT) littermates, Knockout (KO) rats exhibited significantly greater body weight, body circumference, and muscle mass. However, no significant differences in grip force was observed, indicating that Mstn deletion results in greater muscle mass but not greater muscle fiber strength. Additionally, KO rats were found to possess less body fat relative to WT littermates, which is consistent with previous studies in mice and cattle. The aforementioned results indicate that Mstn knockout increases muscle mass while decreasing fat content, leading to observed increases in body weight and body circumference. The Mstn knockout rat model provides a novel means to study the role of Mstn in metabolism and Mstn-related muscle hypertrophy.

The function of myostatin in the regulation of fat mass in mammals

“…Further studies utilizing MSTN transgenic animal models indicated that it mainly promotes fat mass accumulation. For example, MSTN gene knockout in animals mainly leads to reduced fat mass and resistance to diet-induced obesity [39, 41]. MSTN inhibition in animals leads to reductions in fat tissues [46, 48, 49].…”

“…In aging mice, the body fat percentage was also lower in MSTN KO compared with WT [40]. Decreased fat accumulation and increased muscle mass were also observed in MSTN KO rats [41] and pigs compared with wild type animals [42]. Previous research indicated that adipocytes and myocytes are both derived from the same mesodermal precursor [2].…”

Large-scale ruminant genome sequencing provides insights into their evolution and distinct traits

“…SLC9A3R1 affects osteogenesis by mineralizing osteoblasts, and disrupting this gene resulted in reduced body weights in mice (90). MSTN is an important gene in the regulation of muscle cell growth and differentiation (91), and mutations in MSTN affect the muscle mass of goat (92), sheep (93), and cattle (94,95) as well as other mammals (96,97). These results indicate that SLC9A3R1 and MSTN might be targets of natural selection favoring increased body sizes ( fig.…”

Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight

“…Mice carrying a targeted deletion of the Mstn gene exhibit dramatic muscle growth, with individual muscles weighing about twice as much as those of wild type mice ( 2 ). The function of MSTN has been strongly conserved through evolution, as targeted or naturally occurring mutations in cattle ( 3 – 5 ), sheep ( 6 ), dogs ( 7 ), rabbits ( 8 ), rats ( 9 ), swine ( 10 ), and goats ( 11 ) have all been shown to lead to increased muscling. Moreover, a heavily muscled boy was found to carry a mutation in a splice site in the MSTN gene, showing that MSTN plays a similar role in humans as well ( 12 ).…”