Rapamycin suppresses postnatal muscle hypertrophy induced by myostatin-inhibition accompanied by transcriptional suppression of the Akt/mTOR pathway

Abstract

Myostatin (MSTN) is a well-known negative growth factor of muscle mass, and studies have shown that MSTN-inhibition would be a potential strategy to treat muscle atrophy seen in various clinical conditions. Recent studies suggest that MSTN-inhibition induces skeletal muscle hypertrophy through up-regulation of the anabolic Akt/mTOR pathway. Therefore, it was hypothesized that the muscle hypertrophy induced by MSTN-inhibition would be suppressed by the administration of rapamycin (RAP), a mTOR suppressor. A MSTN transgenic mouse strain (MSTN-pro), which is characterized by a postnatal hyper-muscularity due to MSTN inhibition through transgenic overexpression of MSTN propeptide, was used in producing experimental animals. Five-week-old male heterozygous MSTN-pro mice and wild-type littermates were administered with 0 or 3 mg/kg body weight of RAP intraperitoneally every other day for 4 weeks. The effects of RAP on muscle growth, mRNA abundance of signaling components of the Akt/mTOR pathway, and myogenic regulatory factors (MyoD, Myf5, MyoG, and Mrf4) were examined in comparison to wild-type mice. Body weight gain of MSTN-pro mice was significantly greater than that of wild-type mice. RAP suppressed body weight gain and muscle mass in both MSTN-pro and wild-type mice. The extent of both body weight and muscle mass suppression was significantly greater in MSTN-pro mice than in wild-type mice. Real-time qPCR analysis showed that mRNA abundance of the signaling molecules of the Akt/mTOR pathway, including Akt, p70S6K, and 4E-BP1, were significantly higher in MSTN-pro mice. RAP treatment decreased mRNA abundance of Akt, p70S6K and 4E-BP1 only in MSTN-pro mice. mRNA abundances of MyoD and MyoG were not affected by MSTN suppression or RAP treatment. mRNA abundance of Myf5 was decreased by RAP, but not affected by MSTN suppression. mRNA abundance of Mrf4 was decreased by MSTN suppression. RAP treatment decreased mRNA abundance of Mrf4 only in wild type mice. Results of this study indicate that transcriptional regulation of signaling components of the Akt/mTOR pathway and myogenic regulatory transcription factor Mrf4 is involved in the enhancement of skeletal muscle mass induced by MSTN suppression.

Maternal Methyl-Donor Micronutrient Supplementation During Pregnancy Promotes Skeletal Muscle Differentiation and Maturity in Newborn and Weaning Pigs

“…MyoD1 and Myf5 are involved in muscle determination, while Myog plays a predominant role in muscle cell differentiation to form muscle fibers. MRF4 is essential in the maintenance of postnatal muscles (49). MSTN is a negative regulator of skeletal muscle growth (50).…”

Antioxidant and Adaptative Response Mediated by Nrf2 during Physical Exercise

“…Myostatin negatively controls muscular growth [106]; therefore, the repression of the myostatin signaling pathway inhibits the transcription of genes implicated in protein synthesis, stimulating muscular anabolism by means of the regulation of the Akt/mTOR pathway [90,107,108]. The transcriptional modulation of components of the Akt/mTOR pathway (Akt, p70S6K, and 4E-BP1), as well as of the myogenic regulator factor Mrf4, are involved in the increase of the musculoskeletal mass induced by the suppression of myostatin [109]. The apparent enlargement of muscle-cell size is due, in part, to the phenomenon of “cell swelling”, due to the osmotic changes, this event is experienced by the rapid contraction fibers.…”

Partial Inhibition of mTORC1 in Aged Rats Counteracts the Decline in Muscle Mass and Reverses Molecular Signaling Associated with Sarcopenia

“…This certainly gave the impression that activation of mTORC1 signaling was desirable for the maintenance of muscle mass. Most recently, it was shown that rapamcycin treatment inhibited muscle mass increase caused by myostatin loss (19). Thus, it seemed reasonable that inhibition of the pathway was not desirable in settings of muscle loss (1, 18, 20).…”