The functional role of calcineurin in hypertrophy, regeneration, and disorders of skeletal muscle

Abstract

Skeletal muscle uses calcium as a second messenger to respond and adapt to environmental stimuli. Elevations in intracellular calcium levels activate calcineurin, a serine/threonine phosphatase, resulting in the expression of a set of genes involved in the maintenance, growth, and remodeling of skeletal muscle. In this review, we discuss the effects of calcineurin activity on hypertrophy, regeneration, and disorders of skeletal muscle. Calcineurin is a potent regulator of muscle remodeling, enhancing the differentiation through upregulation of myogenin or MEF2A and downregulation of the Id1 family and myostatin. Foxo may also be a downstream candidate for a calcineurin signaling molecule during muscle regeneration. The strategy of controlling the amount of calcineurin may be effective for the treatment of muscular disorders such as DMD, UCMD, and LGMD. Activation of calcineurin produces muscular hypertrophy of the slow-twitch soleus muscle but not fast-twitch muscles.

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 [–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.