Journal Title (Medline/Pubmed accepted abbreviation): J Appl Physiol
Page Numbers: 692-701
doi: 10.1152/japplphysiol.0054.2010 8750-7587/10
Summary of Background and Research Design
Background:Organisms experiencing food deprivation (FD) initiate various physiologic mechanisms to maintain blood glucose levels. Skeletal muscle protein serves as a crisis reserve that can be broken down to amino acids and converted into glucose by gluconeogenesis in the liver to help maintain blood glucose level. This results in atrophy of skeletal muscle during FD. Myostatin (MSTN) is a secreted factor expressed by skeletal muscle that inhibits muscle growth/induces atrophy, in part by antagonizing the PI3K/Akt/mTOR pathway. Change in MSTN during FD is dependent on both the duration of FD and the muscle site.
Hypothesis:Because maintenance of blood glucose is a critical physiologic priority, MSTN inactivation would not affect muscle mass loss with FD, because it must be compensated for by multiple redundant pathways
Subjects: Wild type C-57 and MSTN-/- mice 2.5 to 3.5 months old
Experimental design: In vivo animal study
Treatments and protocol:After ad libitum access to food, wild type C57 mice were FD for 2 days or FD for 2 days followed by ad libitum access to food for 2 days (FD plus Refed). MSTN-/- mice were fed ad libitum, food deprived for 1 day, or food deprived for 2 days. Mice were killed and the fast-twitch/glycolytic tibialis anterior (TA) muscle and the slow-twitch/oxidative soleus (Sol) muscle were harvested. Analyses included quantitation of mRNA (quantitative reverse-transcriptase polymerase chain reaction [qRT-PCR]) for MSTN, atrogin-1, muscle ring finger 1 (MuRF-1), glucokinase, and phosphoenolpyruvate carboxykinase (PEP-CK), protein (Western blotting), and serum levels of corticosterone and glucose. MuRF-1 and atrogin-1 are ubiquitin ligases that are involved in proteasome-dependent protein degradation.
Summary of research findings:
- Two days of FD significantly decreased TA mass but only modestly and nonsignificantly decreased Sol mass
- Expression of both atrogin-1 and MuRF-1 mRNA was significantly increased in TA by FD but was unaffected in Sol
- MSTN mRNA levels in TA were significantly increased ~300% by day 2, but not day 1, of FD and returned to fed levels after 2 days of refeeding; MSTN RNA levels in Sol were not significantly affected by FD or refeeding
- TA mass decreased to a similar amount after 1 day of FD in wild-type mice and mice null for the MSTN gene but was decreased to a greater degree in wild-type than MSTN-/- mice by 2 days of FD
- Blood glucose levels decreased and corticosterone levels increased to a greater extent in MSTN-/- mice after 2 days of FD; surprisingly, however, muscle MuRF-1 and atrogin-1 mRNA levels were not affected by the lack of MSTN during FD
- Levels of glucokinase mRNA significantly decreased and levels of PEPCK mRNA significantly increased in response to 2 days of FD in both wild-type and MSTN-null mice, with no difference between the 2 genotypes
- The data are consistent with the hypothesis that MSTN is dispensable for the initial atrophy occurring in response to FD but attenuates the decrease in fast-twitch muscle mass during prolonged FD
Interpretation of findings/Key practice applications:
2 days of FD caused a significant decrease in body mass, muscle mass, and total protein content and a significant increase in atrogene expression in TA but not Sol muscle. The muscle-specific effect of FD on MSTN expression in TA and Sol mirrored the differences in muscle mass, protein content, and atrogene expression changes after FD in wild type and MSTN-/- mice. Thus, MSTN appears to be disposable for the loss in muscle mass during the initial aspects of FD but contributes to the loss in TA muscle mass during prolonged FD states.