Calcium Signaling and Activity Dependent Muscle Remodeling

The remarkable adaptability of skeletal muscle is achieved by a highly regulated gene transcription program responsive to differential neuromuscular activity (Fig. 1). In muscle, neural activity is converted into unique calcium transients. The nature and oscillations of intracellular Ca2+ levels specified by neural inputs then determines myofiber type and size by activating specific transcriptional programs. Two sets of Ca2+-sensitive enzymes, calcium/calmodulin-dependent protein kinase (CaMK) and calcineurin phosphatase (PP2B), play major roles in mediating neural activity-dependent fiber specification and remodeling [reviewed in Bassel-Duby and Olson (2006)]. Slow frequency oscillations in intracellular calcium have been proposed to activate calcineurin. Activated calcineurin then dephosphorylates

Fig. 1 Skeletal muscle remodeling under physiological and pathological conditions

NFAT transcription factors, leading to transcription of several slow fiber-specific genes (Chin et al. 1998). However, the calcineurin-NFAT axis is clearly not sufficient to specify the entire slow fiber-type specific transcription program [reviewed in Spangenburg and Booth (2003)]. The second transcription pathway involving CaMK and myocyte enhancer factor-2 (MEF2) transcription is the key determinant of fiber specification in response to neural activity.

Members of MEF2 are MADS box-containing proteins initially identified as transcription factors that cooperate with MyoD-related myogenic factors to promote skeletal muscle differentiation (Molkentin et al. 1995). Alone, MEF2 is unable to initiate transcription of myogenic genes (Molkentin et al. 1995). Nonetheless, MEF2 DNA-binding sites are found flanking numerous skeletal muscle-specific genes, supporting a critical role for MEF2 in the muscle transcription program (Black and Olson 1998). In Drosophila, a single MEF2 exists and its mutation prevents myoblast differentiation and muscle formation (Lilly et al. 1995). In vertebrates, there are four MEF2 genes (A-D) in skeletal muscle. Studies of trans-genic mice carrying a tandem MEF2 binding element-driven LacZ reporter revealed that MEF2 is active in all embryonic muscles, consistent with its role in promoting myogenesis. In contrast, in adult muscle this reporter is selectively active in soleus muscle, which primarily consists of slow-oxidative fibers, and largely inactive in muscle consisting of fast-glycolytic fibers, such as extensor digitorum longus (EDL) (Wu et al. 2000). Interestingly, the MEF2-LacZ reporter can be activated in EDL if muscles are subject to prolonged motor nerve stimulation or exercise training, a regimen that promotes a fast-glycolytic to slow-oxidative fiber transition (Wu et al. 2000, 2001). This elegant reporter study reveals that MEF2 is selectively more active in adult muscle of slow/oxidative fibers and this activity can be regulated by neural inputs. In agreement with this supposition, the soleus-specific expression of slow myosin light chain (MLCslow) requires both

MEF2-binding element in its promoter and proper innervation. Surgical denerva-tion abrogates both MLCslow expression and MEF2 activity in soleus (Esser et al. 1999). These findings suggest an instructive role for MEF2 in specifying myofiber phenotype controlled by neural inputs.

Fiber-type-selective MEF2 activity is established in a posttranslational manner. MEF2 protein levels are similar in different muscle types. The control of fiber-specific MEF2 activity likely involves both calcineurin and CaMK family members, which positively regulate MEF2 transcriptional activity (Wu et al. 2000). In mice, transgenic expression of a constitutively active CaMKIV in skeletal muscle dramatically induces mitochondrial biogenesis consistent with a slow-oxidative fiber phenotype (Wu et al. 2002). While CaMKIV is not normally expressed in skeletal muscle, other CaMK members could play an important role in muscle fiber-type specification. Among them, CaMKII activity is uniquely sensitive to the frequency of calcium oscillation and can be activated by depolarization in response to neural inputs (De Koninck and Schulman 1998). Consistent with its role in relaying neural activity, both Drosophila and mammalian CaMKII are present at the neuromuscular junctions (NMJ), the specialized synapses formed between motor neuron axons and myofibers (Koh et al. 1999). In principle, CaMKII would decode differential neural activities, phosphorylate specific substrates, and modify MEF2-dependent muscle gene expression programs. In this context, the CaMKII substrates would be important components that control activity-dependent muscle remodeling.

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