Figure 3

PGC-1α in aging-related denervation/reinnervation cycles: a hypothetical mechanism. In adult muscle (1), PGC-1α is known to regulate expression of proteins involved in neuromuscular junction integrity, such as muscle-specific kinase (MuSK) and three acetylcholine receptor subunits. We hypothesize that decline in PGC-1α expression with aging (see Figure 2) leads to a decreased expression of MuSK and acetylcholine receptor subunits (2), therefore promoting neuromuscular instability (3) and subsequent loss of innervation and decrease in fiber size (4). We also hypothesize that changes in cellular conditions secondary to denervation (namely, an increase in mitochondrial reactive oxygen species generation) promotes an increase in PGC-1α expression which ultimately, through an increase in the expression of MuSK and acetylcholine receptor subunits (5), promotes muscle fiber reinnervation and partial recovery of fiber size (6). At advanced stages of aging, the blunted response of PGC-1α may prevent successful reinnervation and therefore aggravate the decrease in fiber size (5). PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha.