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.
Highlights
Myostatin (MSTN), known as a growth and differentiation factor-8 (GDF-8), is a member of the transforming growth factor-beta (TGF-ß) superfamily and negatively regulates skeletal muscle mass [1,2]
The body weight of MSTN-pro mice at 2 weeks of RAP treatment was not significantly different from that of wild type mice not treated with RAP (Table 2), suggesting that the increased body mass by MSTN is primarily due to the Akt/Mechanistic target of rapamycin (mTOR) pathway, a signaling pathway suppressed by RAP
If Mrf4 is a negative regulator of muscle growth, the decrease in mRNA abundance of Mrf4 in MSTN-pro mice in this study suggests that MSTN potentially up-regulates the Mrf4 to suppress muscle hypertrophy
Summary
Myostatin (MSTN), known as a growth and differentiation factor-8 (GDF-8), is a member of the transforming growth factor-beta (TGF-ß) superfamily and negatively regulates skeletal muscle mass [1,2]. MSTN regulates muscle growth by controlling muscle fiber numbers during the embryonic and fetal development, as well as by controlling the size of muscle fibers postnatally [9]. Like other members of the TGF- ß superfamily, MSTN signals through Smad complex activated by heteromeric complexes of type I and type II serine/threonine kinase receptors. Even though the Smad signaling pathway activated by MSTN has been well established, the molecular mechanism (s) by which Smads activation regulates skeletal muscle development and growth is not fully elucidated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
