Independent Signals Control Expression of the Calcineurin Inhibitory Proteins MCIP1 and MCIP2 in Striated Muscles

Abstract

Calcineurin, a calcium/calmodulin-regulated protein phosphatase, modulates gene expression in cardiac and skeletal muscles during development and in remodeling responses such as cardiac hypertrophy that are evoked by environmental stresses or disease. Recently, we identified two genes encoding proteins (MCIP1 and MCIP2) that are enriched in striated muscles and that interact with calcineurin to inhibit its enzymatic activity. In the present study, we show that expression of MCIP1 is regulated by calcineurin activity in hearts of mice with cardiac hypertrophy, as well as in cultured skeletal myotubes. In contrast, expression of MCIP2 in the heart is not altered by activated calcineurin but responds to thyroid hormone, which has no effect on MCIP1. A approximately 900-bp intragenic segment located between exons 3 and 4 of the MCIP1 gene functions as an alternative promoter that responds to calcineurin. This region includes a dense cluster of 15 consensus binding sites for NF-AT transcription factors. Because MCIP proteins can inhibit calcineurin, these results suggest that MCIP1 participates in a negative feedback circuit to diminish potentially deleterious effects of unrestrained calcineurin activity in cardiac and skeletal myocytes. Inhibitory effects of MCIP2 on calcineurin activity may be pertinent to gene switching events driven by thyroid hormone in striated muscles. The full text of this article is available at http://www. circresaha.org.

Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression

“…4k) and protein (Supplementary Fig. 9d) expression, indicating excessive activation of calcineurin/NFAT signalling in Myoscape KO hearts in response to increased biomechanical stress32. Consistently, Myoscape KO mice showed enhanced fibrosis after aortic constriction, as shown by sirius red stainings of heart sections (Supplementary Fig.…”

“…Despite decades of research, heart failure remains a major cause of death and mortality32333435363738. Therefore, improved understanding of the molecular mechanisms underlying heart failure is still urgently needed to develop novel targeted treatment strategies.…”

Key signalling factors and pathways in the molecular determination of skeletal muscle phenotype

“…AKAP79, cain/cabin 1, and CBHP are ubiquitous factors and were found to inhibit NFAT function or translocation to the nucleus (Crabtree, 2001). More recently, two additional endogenous calcineurin-specific inhibitors (DSCR1/MCIP1 and ZAKI-4/DSCR1L1/MCIP2), highly expressed in striated muscles and brain, were found (Yang et al, 2000;Rothermel et al, 2001). DSCR1 expression is induced by calcineurin and hence forms a negative feedback loop to limit calcineurin activation Signalling and pathways in molecular determination of skeletal muscle phenotype (Yang et al, 2000).…”

“…More recently, two additional endogenous calcineurin-specific inhibitors (DSCR1/MCIP1 and ZAKI-4/DSCR1L1/MCIP2), highly expressed in striated muscles and brain, were found (Yang et al, 2000;Rothermel et al, 2001). DSCR1 expression is induced by calcineurin and hence forms a negative feedback loop to limit calcineurin activation Signalling and pathways in molecular determination of skeletal muscle phenotype (Yang et al, 2000). Its over-expression in transgenic mice prevented cardiac hypertrophy Van Rooij et al, 2004).…”

Recent research developments in regeneration of skeletal muscle

“…SRF also enhances the hypertrophic process in muscle fibers 81,82) . For example, the authors showed that, in mechanically overloaded rat muscles, SRF protein is coing particularly abundant in slow-twitch muscle, but not detectable in fast-twitch glycolytic muscles 54,55) . More recently, reporter assays using cultured myoblasts indicated that the transcriptional activation of NFAT by calcineurin was also inhibited by calsarcin-2 56) .…”