The Functional Role of Calcineurin in Hypertrophy, Regeneration, and Disorders of Skeletal Muscle

Figure 1

Schematic diagram of calcineurin signaling to regulate hypertrophy and regeneration of skeletal muscle. Mechanical loading of skeletal muscle increase intracellular Ca²⁺ levels via the influx (L-type Ca²⁺ channel) of Ca²⁺ from the extracellular space and its efflux from the sarcoplasmic reticulum. The damage of muscle fiber membrane after treatment with myotoxin also elicits an increase in intracellular Ca²⁺ levels via the influx of Ca²⁺ from the extracellular space. Binding of the Ca²⁺/CaM complex to the calcineurin regulatory subunit leaded to its activation. Activated calcineurin dephosphorylates NFATc1 [26, 65, 70], NFATc3 [23], MEF2C [59], and MEF2A [29, 70] resulting in their translocation from the cytoplasm to the nucleus. These transcription factors induce the expression of hypertrophic and/or remodeling genes such as Dev MHC [29], 𝛼-actin, IGF-I [71], myogenin [25], and IL-6 [72]. In addition, activated calcineurin inhibits the functional role of Egr-1 [25] and myostatin [32–34]. Mechanical overloading upregulates gene expression of IGF-I. IGF-I modulates calcineurin signaling via increasing intracellular Ca²⁺ levels [25] and activating GATA-2 [50, 73]. MCIP1 [58] and calsarcin-2 [17] are potent inhibitors of calcineurin signaling. MEF2A: Myocyte enhancer factor 2A; NFATc1: nuclear factor of activated T cells c1; MCIP1: Modulatory calcineurin-interacting protein 1; IRS-1: Insulin receptor substrate-1; PI3-K: Phosphatidylinositol 3-kinase; CaM: Calmodulin; Dev MHC: Developmental myosin heavy chain; IL-6: Interleukin-6.