Combinatory effects of siRNA-induced myostatin inhibition and exercise on skeletal muscle homeostasis and body composition

Abstract

Inhibition of myostatin (Mstn) stimulates skeletal muscle growth, reduces body fat, and induces a number of metabolic changes. However, it remains unexplored how exercise training modulates the response to Mstn inhibition. The aim of this study was to investigate how siRNA‐mediated Mstn inhibition alone but also in combination with physical activity affects body composition and skeletal muscle homeostasis. Adult mice were treated with Mstn‐targeting siRNA and subjected to a treadmill‐based exercise protocol for 4 weeks. Effects on skeletal muscle and fat tissue, expression of genes, and serum concentration of proteins involved in myostatin signaling, skeletal muscle homeostasis, and lipid metabolism were investigated and compared with Mstn −/− mice. The combination of siRNA‐mediated Mstn knockdown and exercise induced skeletal muscle hypertrophy, which was associated with an upregulation of markers for satellite cell activity. SiRNA‐mediated Mstn knockdown decreased visceral fat and modulated lipid metabolism similar to effects observed in Mstn −/− mice. Myostatin did not regulate its own expression via an autoregulatory loop, however, Mstn knockdown resulted in a decrease in the serum concentrations of myostatin propeptide, leptin, and follistatin. The ratio of these three parameters was distinct between Mstn knockdown, exercise, and their combination. Taken together, siRNA‐mediated Mstn knockdown in combination with exercise stimulated skeletal muscle hypertrophy. Each intervention or their combination induced a specific set of adaptive responses in the skeletal muscle and fat metabolism which could be identified by marker proteins in serum.

Comparative analysis of silencing expression of myostatin (MSTN) and its two receptors (ACVR2A and ACVR2B) genes affecting growth traits in knock down chicken

“…The significantly higher magnitudes were observed in MSTN - ACVR2B (38.4 ± 2.9%) and MSTN - ACVR2A (33.9 ± 1.9%) knock down birds for breast muscle and MSTN (27.1 ± 3.1%) and ACVR2B (27.0 ± 0.5%) knock down birds for leg muscle over control group of birds (27.6 ± 2.1 and 19.3 ± 1.3%, respectively). The similar trend of muscular hypertrophy was observed in MSTN knock down in Zebra fish 37 , catfish 38 and human 39 revealing importance gene silencing for MSTN for enhancing growth.…”

Glucocorticoids Enhance Muscle Proteolysis through a Myostatin-Dependent Pathway at the Early Stage

“…The absence of both insulin and IGF-I in the cultural media should be a reason of the unaffected mTOR/p70S6K in follostatin treatment. Therefore, the role of myostatin and follistatin in glucocorticoid-induced muscle development and growth remains to be elucidated with gene interfering technique in future [ 53 ].…”

Sex differences in body composition but not neuromuscular function following long-term, doxycycline-induced reduction in circulating levels of myostatin in mice

“…The effects of chronic DOX treatment on body composition in mice had not been published at the start of the study (2013); however, in 2017 Wang et al [69] reported decreased fat mass accumulation with ten weeks of DOX treatment in male db/db mice. A major benefit of MSTN reduction therapy is improved body composition, as increased lean mass and decreased fat mass has been reported in constitutive knock-out mice [70,71], while post-developmental models indicate that MSTN reduction prevents fat mass accumulation but does not reduce existing fat mass levels [24,72,73]. DOX treatment, therefore, is potentially a major confounding factor when body composition changes are primary endpoints of a study.…”