Calcineurin is not involved in muscle mass maintenance during atrophy
M. Knox, E.E. Dupont-Versteegden
Dept. Geriatrics,
Center on Aging,
University of Arkansas for Medical Sciences,
Little Rock, AR 72205
Muscle size and the ability to maintain muscle mass declines with age and the underlying mechanisms are largely unknown. The goal of this study was to investigate the calcineurin pathway, which is known to influence skeletal muscle hypertrophy, and to study its involvement in atrophy and maintenance of muscle mass. To induce atrophy, rats (6 months of age) were hind limb suspended (HS) for two weeks; to prevent the loss of muscle mass in the face of the atrophying event, a group of the rats was intermittently reloaded (HSIR) 1 hour each day for two weeks. Cyclosporine (CYC) was injected to inhibit calcineurin activity at a dose of 25mg/kg/day in control, not suspended (CON), HS and HSIR groups. After two weeks, soleus muscles were dissected, weighed and frozen for determination of muscle fiber cross sectional area (CSA), fiber typing, and RNA analysis. Blood was drawn for measurement of cyclosporine. Serum cyclosporine levels were undetectable in animals not injected and there was no difference in serum cyclosporine between the injected groups (CONCYC: 7020 ± 1121, HSCYC: 4880 ± 1405, HSIRCYC: 6032 ± 1212 ng/ml). Muscle to body mass ratio was decreased with HS (CON: 0.405 ± 0.026 mg/g; HS: 0.284 ± 0.004 mg/g) and partly maintained with HSIR (0.317 ± 0.007mg/g). Cyclosporine treatment did not significantly alter the effect of HS or HSIR on muscle mass. CSA of soleus muscles was decreased upon hind limb suspension (CON: 3751 ± 112; HS: 2766 ± 117 um2) and HSIR increased CSA slightly, but not significantly (HSIR: 2835 ± 148 um2). Cyclosporine did not affect the changes in muscle size upon experimental conditions. Control soleus muscles were mainly composed of type 1 myosin heavy chain (MyHC) expressing fibers and some expression of type 2a. However, no type 2x MyHC was observed in control muscles. Cyclosporine induced the expression of MyHC 2x in soleus muscles of some rats, but not all. Fibers expressing MyHC 2x were also expressing MyHC type 1 or 2a. No change in calcineurin gene expression was observed with cyclosporine treatment.
Results suggest that calcineurin is not involved in the maintenance of muscle size in the face of an atrophy-inducing event, but may be responsible for some of the fiber type changes observed. Further studies are warranted to investigate other pathways responsible for maintenance of muscle mass.
Key words:
skeletal muscle, atrophy, calcineurin, hindlimb suspension, cyclosporine
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