Role of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in denervation-induced atrophy in aged muscle: facts and hypotheses

Abstract

Aging-related loss of muscle mass, a biological process named sarcopenia, contributes to mobility impairment, falls, and physical frailty, resulting in an impaired quality of life in older people. In view of the aging of our society, understanding the underlying mechanisms of sarcopenia is a major health-care imperative. Evidence obtained from human and rodent studies demonstrates that skeletal muscle denervation/reinnervation cycles occur with aging, and that progressive failure of myofiber reinnervation is a major cause of the accelerating phase of sarcopenia in advanced age. However, the mechanisms responsible for the loss of myofiber innervation with aging remain unknown. The two major strategies that counteract sarcopenia, that is, caloric restriction and endurance training, are well known to protect neuromuscular junction (NMJ) integrity, albeit through undefined mechanisms. Interestingly, both of these interventions better preserve PGC-1α expression with aging, a transcriptional coactivator which has recently been shown to regulate key proteins involved in maintaining NMJ integrity. We therefore propose that the aging-related decline in PGC-1α may be a central mechanism promoting instability of the NMJ and consequently, aging-related alterations of myofiber innervation in sarcopenia. Similarly, the promotion of PGC-1α expression by both caloric restriction and exercise training may be fundamental to their protective benefits for aging muscle by better preserving NMJ integrity.

Figure 1

Aging-related changes of the neuromuscular system: the central role of denervation. To illustrate the main aging-related changes of the neuromuscular system that identify denervation as a primary cause of sarcopenia, schematic representations of adult (A) and aged (B) neuromuscular systems are presented. Key features of neuromuscular aging, all indicative of denervation, are highlighted as follow: loss of motor neurons (normally located in lamina IX of the spinal cord; not represented for clarity purposes) (1), decrease in both axon number and diameter (2), fiber type grouping (3), increase in myosin heavy chain co-expression (4), and appearance of fragmented or denervated neuromuscular junctions (5). See main text for more details.

Figure 2

Aging-related changes in PGC-1α and muscle-specific kinase (MuSK). (A) Aging-related changes in PGC-1α expression. Data adapted from [69] (with permission from Oxford University Press), where PGC-1α expression was determined in gastrocnemius muscle of young adult (YA; 8 to 10 months) late middle-aged (LMA; 30 months) and senescent (SEN; 35 months) Fisher 344/Brown Norway F1 hybrids rats. Note the dramatic decrease in muscle PGC-1α expression from adulthood to LMA and its partial recovery from LMA to SEN. (B) Evidence for aging-related decrease in MuSK content at the neuromuscular junction (NMJ). MuSK protein content at the NMJ was determined in situ by immunolabeling plantaris cross-sections from YA (6 months) and SEN (35 months) rats with DAPI (labeling nuclei - blue in merge image), α-bungarotoxin (labeling acetylcholine receptors - green in merge image), and anti-MuSK antibody (kindly provided by Dr. Markus Rüegg; red in merge image) using protocols we previously described [22,57]. A control slide, for which the incubation with the anti-MuSK antibody was omitted, is presented at the bottom of panel B. White arrows point toward a NMJ having very low MuSK protein content in SEN muscle. (C) Aging-related changes in PGC-1α determined in situ. Cross-sections of the white (glycolytic) gastrocnemius region of one YA and SEN rat were immunolabeled for PGC-1α (green), dystrophin (red) and nuclei (blue) according to methods described in [22]. The anti-PGC-1α antibody was purchased from Millipore (AB3242; Millipore, Billerica, MA, USA). PGC-1α content was quantified by tracing each fiber using ImageJ (images on the right). A control slide, for which incubation with the anti-PGC-1α antibody was omitted, is presented at the bottom. The graph on the right presents PGC-1α content as a function of fiber size. *P <0.05 vs. YA, ^#P <0.05 vs. small fibers (<1000 μm²). DAPI, 4′,6′-diamidino-2-phénylindole; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha.

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.