Other Signaling Pathways in Skeletal Muscle Remodeling

Peroxisome proliferator-activated receptor delta (PPAR8) and its coactivator peroxisome proliferator-activated receptor coactivator-1 alpha (PGC-1a) are key regulators of genes involved in mitochondria and oxidative metabolism in skeletal muscle. Expression of PGC-1a is higher in type I fibers. One study showed that PGC-1a mRNA levels are ~5-fold higher in soleus (slow-oxidative fibers) than gastrocnemius (mixed) or EDL (fast-glycolytic fibers) muscle. Supporting an instructive role for PGC-1a and PPAR8 in oxidative fiber phenotype overexpression of PGC-1a or PPAR8 increases the number of slow-oxidative fibers type I myofibers (Koves et al. 2005; Lin et al. 2002; Grimaldi 2003). Transgenic overexpression of PGC-1a also causes fast-glycolytic fibers to become more resistant to atrophy. The PGC1-a promoter contains several MEF2 binding sites and its expression can be repressed by HDAC5 and HDAC4 (Czubryt et al. 2003). The regulation by the HDAC4, -5/MEF2 complex could explain the more abundant expression of PGC1-a in slow-oxidative fibers and after exercise, as well as reduced expression in denervated muscle (Koves et al. 2005; Sandri et al. 2006).

MAPK pathways are also coupled to electrical stimulation, affecting both fiber type and size (Aronson et al. 1997; Murgia et al. 2000). Electrical stimulation transiently increases JNK activity via the MEKK1-MKK4 cascade with JNK activity peaking within 30 min following stimulation (Aronson et al. 1997). JNK activation leads to an increase in c-jun mRNA levels; however, the physiological significance of this pathway remains unclear. Over a longer period of time (3-10 days), low-frequency electrical stimulation results in activation of Ras signaling, which proceeds through a MAPK (ERK) pathway. Interestingly, the Ras-MAPK (ERK) pathway promotes transition to type I myofibers in a muscle regeneration model; however, does not greatly affect fiber size (Murgia et al. 2000). In contrast, it was also reported that extracellular signal-regulated kinase (ERK) pathway is preferentially activated in fast-glycolytic fibers and is required for the maintenance of this fiber type (Shi et al. 2008).

The final kinase pathway that deserves mention in muscle remodeling involves protein kinase B (PKB)/Akt and mammalian target of rapamycin (mTOR). Upon loss of neural input, the activity of Akt is greatly diminished (Pallafacchina et al. 2002). As opposed to the Ras-MAPK pathway, activation of Akt increases myofiber size without affecting fiber type. Akt signaling proceeds through mTOR, as rapamycin is able to ablate the effects of activated Akt on muscle fiber size. Interestingly, this pathway is responsible for muscle hypertrophy occurring in response to muscle overload, such as weightlifting. mTOR phosphorylates its targets, p70S6K and PHS-1/4E-BP1, in order to increase protein synthesis and myofiber size. A number of different stimuli can activate this pathway, including growth factors such as insulin-like growth factor-I (IGF-1). Thus, it seems kinase signaling, especially the Ras-MAPK and Akt-mTOR pathways, provide additional mechanisms to fine-tune myofiber size and type. Whether and how class IIa HDACs are linked to Ras-MAPK and mTOR-AKT signaling axis remains to be established.

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