Remodeling muscles with calcineurin

Ca²⁺ signaling plays a central role in hypertrophic growth of cardiac and skeletal muscle in response to mechanical load and a variety of signals. However, the mechanisms whereby alterations in Ca²⁺ in the cytoplasm activate the hypertrophic response and result in longterm changes in muscle gene expression are unclear. The Ca²⁺, calmodulin-dependent protein phosphatase calcineurin has been proposed to control cardiac and skeletal muscle hypertrophy by acting as a Ca²⁺ sensor that couples prolonged changes in Ca²⁺ levels to reprogramming of muscle gene expression. Calcineurin also controls the contractile and metabolic properties of skeletal muscle by activating the slow muscle fiber-specific gene program, which is dependent on Ca²⁺ signaling. Transcription factors of the NFAT and MEF2 families serve as endpoints for the signaling pathways whereby calcineurin controls muscle hypertrophy and fiber-type. We consider these findings in the context of a model for Ca²⁺-regulated gene expression in muscle cells and discuss potential implications of these findings for pharmacologic modification of cardiac and skeletal muscle function. (C) 2000 John Wiley and Sons, Inc.