Denervation drives mitochondrial dysfunction in skeletal muscle of octogenarians.
Mitochondria are frequently implicated in the ageing of skeletal muscle, although the role of denervation in modulating mitochondrial function in ageing muscle is unknown. We show that increased sensitivity to apoptosis initiation occurs prior to evidence of persistent denervation and is thus a primary mitochondrial defect in ageing muscle worthy of therapeutic targeting. However, at more advanced age, mitochondrial function changes are markedly impacted by persistent sporadic myofibre denervation, suggesting the mitochondrion may be a less viable therapeutic target.



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.
Research Institute of the McGill University Health Centre, Montreal, Canada.|McGill Research Centre for Physical Activity & Health, McGill University, Montreal, Canada.
Sally
S
Spendiff
Research Institute of the McGill University Health Centre, Montreal, Canada.|McGill Research Centre for Physical Activity & Health, McGill University, Montreal, Canada.
Madhusudanarao
M
Vuda
Research Institute of the McGill University Health Centre, Montreal, Canada.|Present address: Department of Kinanthropologie, Universite du Quebec a Montreal, Montreal, Canada.
Gilles
G
Gouspillou
Research Institute of the McGill University Health Centre, Montreal, Canada.|McGill Research Centre for Physical Activity & Health, McGill University, Montreal, Canada.
Sudhakar
S
Aare
Research Institute of the McGill University Health Centre, Montreal, Canada.
Anna
A
Perez
Division of Geriatric Medicine, McGill University, Montreal, Canada.
José A
JA
Morais
Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Canada.
Robert T
RT
Jagoe
Department of Kinesiology & Physical Education, McGill University, Montreal, Canada.
Marie-Eve
ME
Filion
Department of Kinesiology & Physical Education, McGill University, Montreal, Canada.
Robin
R
Glicksman
Department of Kinesiology & Physical Education, McGill University, Montreal, Canada.
Sophia
S
Kapchinsky
Department of Kinesiology & Physical Education, McGill University, Montreal, Canada.
Norah J
NJ
MacMillan
Present address: Department of Kinanthropologie, Universite du Quebec a Montreal, Montreal, Canada.
Charlotte H
CH
Pion
Present address: Department of Kinanthropologie, Universite du Quebec a Montreal, Montreal, Canada.
Mylène
M
Aubertin-Leheudre
Neurotune, Zurich, Switzerland.
Stefan
S
Hettwer
Department of Mathematics and Statistics, McGill University, Montreal, Canada.
José A
JA
Correa
McGill Research Centre for Physical Activity & Health, McGill University, Montreal, Canada.|Department of Kinesiology & Physical Education, McGill University, Montreal, Canada.
Tanja
T
Taivassalo
Research Institute of the McGill University Health Centre, Montreal, Canada.|McGill Research Centre for Physical Activity & Health, McGill University, Montreal, Canada.|Department of Kinesiology & Physical Education, McGill University, Montreal, Canada.
Russell T
RT
Hepple
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism*; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000294:innervation* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D055815:Young Adult
D017382:Reactive Oxygen Species
aging; denervation; mitochondria; muscle atrophy; neuromuscular junction; sarcopenia