Figure 6. Simplified scheme of the stimulus pattern-dependent transcription through Ca²⁺ activated pathways.

A, frequent activity mimicking that experienced by slow-twitch muscle fibres in vivo results in a Ca²⁺ binding to calmodulin (CaM) that is sufficient to induce a prolonged activation of CaN and CaMKII. Activated CaN controls transcription by inducing nuclear translocation of NFAT (Bassel-Duby & Olson, 2006) to promote transcription of slow type-specific genes, such as slow isoforms of myosin heavy chain and troponin I (Dunn et al. 1999; Serrano et al. 2001). Activated CaMKII stimulates transcription by removing repressive HDAC from the nucleus and by phosphorylating MEF2 (Bassel-Duby & Olson, 2006). MEF2 suppresses the myogenesis when it forms a complex with HDAC, but upon CaMKII-dependent disruption of MEF2-HDAC-complexes, MEF2 activates transcription (McKinsey et al. 2000) in co-operation with NFAT (Wu et al. 2000). When activated, Ca²⁺-dependent cascades also promote mitochondrial biogenesis via activation of PGC-1α (Wu et al. 2002). B, infrequent activation similar to that experienced by fast-twitch muscle fibres in vivo allows CaN and CaMKII deactivation between contractions. As a result, NFAT is not translocated into the nucleus, which suppresses the slow type of gene expression. In addition, HDAC remains in the nucleus and forms complexes with MEF2, which further suppresses slow type gene expression. Thus, this type of stimulation favours the expression of fast type-specific protein isoforms and it does not stimulate mitochondrial biogenesis; however, it does not promote the same phenotype as total lack of stimulation, which in addition involves muscle atrophy and weakness. Arrows indicate stimulatory actions, whereas dotted lines indicate lack of activation.