Denervation drives mitochondrial dysfunction in skeletal muscle of octogenarians

Abstract

Experimental denervation modulates mitochondrial function, where changes in both reactive oxygen species (ROS) and sensitivity to permeability transition are implicated in the resultant muscle atrophy. Notably, although denervation occurs sporadically in ageing muscle, its impact on ageing muscle mitochondria is unknown. Because this information has important therapeutic implications concerning targeting the mitochondrion in ageing muscle, we examined mitochondrial function in skeletal muscle from four groups of humans, comprising two active (mean ± SD age: 23.7 ± 2.7 years and 71.2 ± 4.9 years) and two inactive groups (64.8 ± 3.1 years and 82.5 ± 4.8 years), and compared this with a murine model of sporadic denervation. We tested the hypothesis that, although some alterations of mitochondrial function in aged muscle are attributable to a primary organelle defect, mitochondrial dysfunction would be impacted by persistent denervation in advanced age. Both ageing in humans and sporadic denervation in mice increased mitochondrial sensitivity to permeability transition (humans, P = 0.004; mice, P = 0.01). To determine the contribution of sporadic denervation to mitochondrial function, we pharmacologically inhibited the denervation-induced ROS response. This reduced ROS emission by 60% (P = 0.02) in sporadically denervated mouse muscle, which is similar to that seen in humans older than 75 years (-66%, P = 0.02) but not those younger than 75 years. We conclude that an increased sensitivity to permeability transition is a primary mitochondrial defect in ageing muscle. However, at more advanced age, when muscle atrophy becomes more clinically severe, mitochondrial function changes are markedly impacted by persistent sporadic denervation, making the mitochondrion a less viable therapeutic target.

Mitochondria Initiate and Regulate Sarcopenia

“…Apoptosis signaling has been reported in muscle and neuronal cells of aged rodents (4, 7, 26, 34, 47, 77, 88, 130), and humans (44, 145). Aging-associated muscle denervation may also contribute to increased mPTP opening, that in turn induces apoptosis and muscle loss (76, 133). …”

“…Mitochondrial stress in aging can originate from greater levels of oxidants, DNA damage, or denervation (31, 133). …”

“…ROS production might be secondary to denervation that occurs in muscles from old animals or humans (48, 55, 133). The accumulation of ROS has the potential to damage cellular mitochondria (reviewed in (15)).…”

Mitochondrial respiratory chain deficiency in older men and its relationship with muscle mass and performance

“…It is also likely that mitochondria reflect prior exposures such as lifetime physical activity [42] which is recognised to be important for muscle function on entering old age [43]. Another possibility is that the mitochondrial respiratory deficiency occurs secondary to a separate pathology such as denervation, as recently demonstrated by Spendiff et al among a sample of the very old [44].…”

Dysfonctions mitochondriales et vieillissement musculaire

“…Notre groupe a mis en évidence que déclenchement de l'apoptose de la cellule par l'ouverture du PTP. L'étude de la réponse des mitochondries soumises à un excès de calcium montre, chez le rat [24] et chez l'homme [23,45], que le vieillissement musculaire s'accompagne d'une réduction de la capacité de rétention en calcium des mitochondries et d'une diminution du temps nécessaire à l'ouverture du PTP. Le vieillissement musculaire s'accompagne donc d'une sensibilisation du PTP, suggérant une propension accrue des mitochondries âgées au déclenchement de l'apoptose.…”