Calcineurin Signaling and Muscle Remodeling

2ϩ-calmodulin, participates in signaling pathways valvular dysfunction, from ischemic injury following cor-important for gene regulation and biological responses onary artery occlusion, or from mutations in genes en-to external stimuli in many organisms and in many types coding proteins of the sarcomere. Initially, this remodel-of cells (Crabtree, 1999). Calcineurin-dependent signal-ing response appears to serve an adaptive purpose; ing events have been studied most intensively in the hyperfunctioning myocytes maintain an equilibrium be-activation of T lymphocytes to foreign antigens, and tween demand and capacity for contractile work. How-drugs that inhibit calcineurin activity are in clinical use ever, when the pathological stimulus is unremitting, the to prevent rejection of transplanted organs. Recently, heart undergoes a transition from a thickened, hypertro-we and our colleagues advanced the hypothesis that phic state to a thin-walled, dilated morphology. Individ-calcineurin plays a central role in transducing environ-ual cardiomyocytes remain hypertrophic, but the normal mental signals that control gene expression and hyper-geometric patterning among myocytes is altered, and trophic growth in cardiac and skeletal muscles (Chin et myocytes dying of apoptosis or necrosis are replaced by al., 1998; Molkentin et al., 1998). This notion has stimu-fibrous tissue. This latter form of remodeling response is lated considerable interest and experimental activity, accompanied by functional deterioration and an inexo-and not a little controversy. The high level of interest rable course leading to death from circulatory collapse has been based both on certain striking experimental or lethal dysrhythmia. Skeletal myopathies also are char-data, and on the potential for manipulation of calcineurin acterized by tissue remodeling and morphological ab-signaling as a therapeutic measure for common and normalities, but these take different forms than those devastating forms of human disease. The controversy exhibited by the heart, in large measure because of a has arisen from apparently discrepant results of experi-capacity for myocyte regeneration that is lacking in the ments designed to test the importance of calcineurin in heart. transduction of different signals that evoke remodeling While the causes and consequences of myocyte hy-responses in striated muscles. Here we provide a brief pertrophy are well known, the underlying signaling path-summary of major experimental results to date, and offer ways and transcriptional mediators of this response are some suggestions as to how results that appear discor-less clear. It is also unknown whether the same intracel-dant may be reconciled. lular pathways control hypertrophy of cardiac and skele-Physiologic and Pathologic Signals tal myocytes and whether physiologically beneficial hy-for …