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.

Role of PGC-1α in Sarcopenia: Etiology and Potential Intervention - A Mini-Review

“…Conversely, PGC-1α and PGC-1β can both reduce phosphorylation of NFκB subunit p65 and weaken its transcriptional potential [31]. However, ROS is also known to activate AMPK and p38, which might activate PGC-1α and thus compensate for the downregulation with age [3]. Figure 2 illustrates the potential regulators of the PGC-1α pathway and its relationship with the NFκB pathway, and how the interactions may affect muscle protein synthesis and degradation.…”

“…Both intrinsic and extrinsic factors contribute to the development of sarcopenia [3]. Intrinsic factors include: (i) a deterioration of protein synthesis required to replace the wasting muscle; (ii) decreased androgen levels, such as testosterone, GH and IGF that stimulate protein synthesis; (iii) increased proteolysis and autophagy due to ROS generation and inflammation; (iv) decline of motor nerve stimulation, including the dysfunction of the neuromuscular junction (NMJ) program, and (v) enhanced apoptosis and decreased satellite and stem cell activities.…”

“…Numerous pathways have been identified to have potential influences on the degeneration of muscle fibers, including hormonal, neural, metabolic and molecular signals that alter their input during aging [2,3]. There is increasing evidence that mitochondrial abnormality plays a crucial role due to their multifaceted functions within the cell [4,5].…”

“…Thus, it is not surprising that much of the current research on sarcopenia has been focused on this critical organelle. Readers are referred to more detailed reviews on the role of mitochondria in sarcopenia [2,3,4,5,7]. …”

Dysfonctions mitochondriales et vieillissement musculaire

“…Elle représente une thématique de recherche actuellement très active. De multiples mécanismes biologiques ont été proposés pour expliquer son développement (voir [3] …”