Primary versus Secondary Mitochondrial Function Alterations in Aging Muscle

Altered mitochondrial function has been implicated in aging muscle atrophy. If this is a primary effect or secondary to sporadic denervation that occurs in aging is unclear. To address this question we examined four groups of human males: young active (YA, 24 yrs), old active (OA, 71yrs), old inactive (OI, 65 yrs) and very old inactive (VOI, 83yrs). We demonstrated that activity and age modified mitochondrial function in myofibres (respiration coupling YA 4.0±0.2 vs OA 3.3±0.2 vs OI 2.9±0.2 vs VOI 2.5±0.1 & calcium retention capacity YA 0.9±0.2 vs OA 0.4±0.1 vs OI 0.3 ±0.01 vs VOI 0.3 ±0.1). To better isolate the impact of denervation on mitochondrial function we used a model of sporadic denervation (sarco mice who have unstable neuromuscular junctions) and a pharmacological approach (arachidonyl trifluoromethyl ketone (AACOCF3)) to block the denervation‐induced mitochondrial ROS (mtROS) signal. Sarco mice treated with AACOCF3 had significantly reduced mtROS emissions compared to vehicle treated myofibers (vehicle, 0.11±0.03 vs. AACOCF3, 0.05±0.03) but not wild type mice, demonstrating that denervation modulates mtROS. In humans, AACOCF3 reduced mtROS in the over 75s (vehicle, 0.7±0.1 vs. AACOCF3, 0.2±0.1) but not in younger subjects. We conclude that while some alterations in mitochondrial function are age related, others are in part, secondary to accumulation of denervated myofibres. This has implications for therapeutic targeting of mitochondria to ameliorate aging muscle atrophy. CIHR MOP119583 & 125986