Understanding Bodybuilding

Repeated use of muscles during exercise results in long-term changes in cellular phenotype: Fast glycolytic myofibers change their metabolic capacity, contractile properties, and size to become slow oxidative myofibers. But what signals bring about such changes and serve to store the "memory" of the cell's past experience? Rosenberg et al. propose that increased expression of the transient receptor potential (TRPC3) channel, a nonselective channel that allows calcium influx across the plasma membrane, may be at the heart of the process. The authors created transgenic mice carrying a reporter gene that allowed them to monitor activity of the calcium-regulated transcription factor NFAT (nuclear factor of activated T cells). A strict training regimen of daily wheel running increased NFAT-dependent transcription in the affected muscles. In cultured cells, the authors showed two types of calcium signals contribute to control of NFAT: Voltage-dependent release of calcium associated with excitation-contraction coupling caused NFAT to move to the nucleus, but its sustained presence in the nucleus required voltage-independent influx of calcium across the plasma membrane. The TRPC3 channel is a candidate to mediate the latter, and expression of the gene encoding TRPC3 was increased in muscle after exercise and was regulated by calcium signals. In fact, if myotube cells were transfected with TRPC3, NFAT-dependent activation of a reporter gene was greater and persisted longer than it did in control cells. The authors propose that activity-dependent expression of TRPC3, which itself is dependent on calcium signaling through NFAT, functions as part of a positive-feedback loop. Thus, relatively stable increases in expression of the gene encoding TRPC3, a key component of the NFAT signaling pathway, enhance the effect of sustained stimulation of the pathway and thereby contribute to stabilization of the exercise-dependent phenotype. P. Rosenberg, A. Hawkins, J. Stiber, J. M. Shelton, K. Hutcheson, R. Bassel-Duby, D. M. Shin, Z. Yan, R. S. Williams, TRPC3 channels confer cellular memory of recent neuromuscular activity. Proc. Natl. Acad. Sci. U.S.A. 101 , 9387-9392 (2004). [Abstract] [Full Text]