Denervation drives mitochondrial dysfunction in skeletal muscle of octogenarians

Sally Spendiff, Madhusudanarao Vuda, Gilles Gouspillou, Sudhakar Aare, Anna Perez, José A. Morais, Robert T. Jagoe, Marie-Eve Filion, Robin Glicksman, Sophia Kapchinsky, Norah J. MacMillan, Charlotte H Pion, Mylène Aubertin-Leheudre, Stefan Hettwer, José A Correa, Tanja Taivassalo, Russell T. Hepple

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30 Scopus citations

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. As 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 age 23.7 (SD 2.7) yr & 71.2 (4.9) yr) and two inactive groups (64.8 (3.1) yr & 82.5 (4.8) yr), and compared this to a murine model of sporadic denervation. We tested the hypothesis that while some alterations of mitochondrial function in aged muscle are attributable to a primary organelle defect, in advanced age, mitochondrial dysfunction would be impacted by persistent denervation. Both ageing in humans, and sporadic denervation in mice, increased mitochondrial sensitivity to permeability transition (Humans P = 0.004; Mice P = 0.01). To ascertain 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, similar to what was 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. This article is protected by copyright. All rights reserved.
Original languageEnglish (US)
Pages (from-to)1-39
Number of pages39
JournalJournal of Physiology
DOIs
StatePublished - Sep 2016

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  • Journal Article

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