Signaling pathways in activity-dependent fiber type plasticity in adult skeletal muscle

Adult fast- and slow-twitch skeletal muscle fibers exhibit characteristic differences in functional properties due to differences in the isoforms and quantities of expression of most muscle proteins. However, these differences may be reversed by chronic electrical stimulation of denervated muscle with the pattern typical of the other fiber type. Here, we review three possible signaling pathways that may contribute to fast to slow fiber type transformation. The first pathway involves cytosolic activation of the Ca(2+) sensitive posphatase calcineurin (CaN) due to elevated cytosolic [Ca(2+)], resulting in dephosphorylation of cytoplasmic NFATc, translocation of dephosphorylated NFATc from cytoplasm into the nucleus and activation of slow fiber gene expression by NFATc in the nucleus. The second pathway involves elevated intranuclear [Ca(2+)] causing the activation of nuclear calmodulin dependent protein kinase, which phosphorylates HDAC within the nucleus and thereby permits nuclear efflux of HDAC, thus decreasing the HDAC suppression of MEF2 activation of slow fiber gene expression. The third possible pathway involves nuclear entry of CaN, dephosphorylation of intranuclear MEF2 and consequent increased activation of slow fiber type gene expression by dephosphorylated MEF2. Evidence for the first two pathways from our studies on adult fast twitch skeletal muscle fibers is briefly reviewed.