Calcineurin Signaling and Muscle Remodeling

Increasingly, research into the mechanisms for muscle remodeling has revealed both new components of individual signaling pathways and the interactive participation of parallel pathways that converge on common downstream effector molecules and on common target genes. With respect to new components of calcineurin signaling pathways in cardiac and skeletal muscles, several recent findings begin to shed light on previously irreconcilable sets of data. For example, the ability of calcineurin to control the functional activity of MEF2 transcription factors, in addition to its effects on NFAT, explains how expression of certain genes can be modulated by calcineurin-dependent signaling in the absence of NFAT binding sites within promoter/enhancer regions (1xCalvo, S., Venepally, P., Cheng, J., and Buonanno, A. Mol. Cell Biol. 1999; 19: 515–525See all References, 20xWu, H., Naya, F.J., McKinsey, T.A., Mercer, B., Shelton, J.M., Chin, E.R., Simard, A.R., Michel, R.N., Bassel-Duby, R., Olson, E.N., and Williams, R.S. EMBO J. 2000; 19: 1963–1973Crossref | PubMedSee all References). The link between calcineurin and MEF2 also may account, at least in part, for recent observations that support a role for calcineurin in promoting myogenic differentiation during development (Friday et al. 2000xFriday, B.B., Horsley, V., and Pavlath, G.K. J. Cell Biol. 2000; 149: 657–665Crossref | Scopus (175)See all ReferencesFriday et al. 2000). Proteins have also been discovered recently that bind calcineurin and inhibit its protein phosphatase activity, thereby providing another means by which calcineurin signaling can be controlled. Two of these—Cabin/Cain and AKAP79—are expressed ubiquitously, while others—MCIP proteins—are expressed selectively in striated muscles. Such inhibitory mechanisms that alter calcineurin signaling may influence responses to calcineurin antagonist drugs in a manner that varies among different tissues.An important question is whether the hypertrophic and gene regulatory effects of calcineurin in striated myocytes are mediated directly by downstream transcription factors like NFAT and MEF2, or whether other substrates are responsible for the effects of calcineurin. Notably, calcineurin is associated with the 1,4,5-trisphosphate (IP3) and ryanodine receptors and regulates expression of the IP3 receptor and plasma membrane Ca2+ pump, which would be expected to have significant effects on Ca2+ handling, contractility, and probably hypertrophic growth (Crabtree 1999xCrabtree, G.R. Cell. 1999; 96: 611–614Abstract | Full Text | Full Text PDFSee all ReferencesCrabtree 1999). It may also be instructive to consider the functions of calcineurin in yeast, where it regulates Ca2+ homeostasis and stress responsiveness by controlling target genes involved in ion fluxes (Stathopoulos and Cyert 1997xStathopoulos, A.M. and Cyert, M.S. Genes Dev. 1997; 11: 3432–3444Crossref | PubMedSee all ReferencesStathopoulos and Cyert 1997). Whether calcineurin acts similarly in muscle cells remains to be determined.In summary, rapid progress has been made in delineating the signaling pathways that influence muscle remodeling responses to environmental or pathological stresses, and multiple layers of regulatory complexity to the pathways for remodeling myocytes in response to intrinsic and extrinsic signaling have been identified (Figure 1Figure 1). Subtle differences in the relative timing or intensity of individual primary signals, in specific features of the metabolic milieu or initial state of the cell, or in genetic background may lead to differences in the degree to which any single pathway is activated to produce similar remodeling responses (e.g., cardiac hypertrophy). This discovery process will continue, but the next phase of work in this field is likely to turn more to the task of unraveling molecular details of the complex interactions among diverse sets of signals, transducers, effectors, primary responses, and secondary responses that ultimately produce different remodeling outcomes in cardiac and skeletal muscles.‡To whom correspondence should be addressed (e-mail: eolson@hamon.swmed.edu).