Deciphering the calcineurin/NFAT signaling pathway in the hypertrophy and fiber type conversions of skeletal muscle

Calcineurin (Cn) is a Ca2+ regulated serine/threonine phosphatase that acts on several cellular targets including the Nuclear Factor of Activated T-cells (NFAT) family of transcription factors. In skeletal muscle, the role of the Cn/NFAT signaling transduction pathway has been implicated in the processes of skeletal muscle hypertrophy and fiber type conversions; however, the role of various Ca2+-regulated NFAT isoforms (NFATc1-c3) has yet to be elucidated. Herein, we characterize the roles of the various Ca2+/Cn-regulated NFAT isoforms (NFATc1-c3) in normal weightbearing as well as functionally overloaded muscles in transgenic mice deficient for either NFATc1 or NFATc3 isoform routes of the Cn/NFAT pathway. Using immunohistochemistry, immunoflorescent nuclear co-localization assays and reverse transcription - polymerase chain reaction (RT-PCR) techniques, we establish a role for NFATc1 in the process of promoting the slower, more oxidative, muscle program during skeletal muscle fiber type conversions, and we identify a putative role for NFATc3 in skeletal muscle hypertrophy, In addition to characterizing the role of Cn-regulated NFAT family members in skeletal muscle, we also studied the role of the Ca2+/CaM-regulated transcription factor cyclic-AMP Response Element Binding (CREB) protein in hopes of identifying a parallel signaling pathway involved in regulating the fast muscle program. By characterizing transgenic mice expressing the recombinant Calmodulin Binding Peptide (CaMBP) in combination with functionally overloaded wild type mice, we identify a possible role for CREB signalling in promoting the fast muscle program. Together, these findings provide evidence for a putative transcriptional mechanism in which signals from the Cn/NFAT pathway and the CaM/CREB pathway converge to govern a myofiber's contractile speed and metabolic profile.