Muscle activity prevents the uncoupling of mitochondria from Ca2+ Release Units induced by ageing and disuse

Abstract In fast-twitch fibers from adult mice Ca 2+ release units (CRUs, i.e. intracellular junctions of excitation-contraction coupling), and mitochondria are structurally linked to each other by small strands, named tethers . We recently showed that aging causes separation of a fraction of mitochondria from CRUs and a consequent impairment of the Ca 2+ signaling between the two organelles. However, whether the uncoupling of mitochondria from CRUs is the result of aging per-se or the consequence of reduced muscle activity remains still unclear. Here we studied the association between mitochondria and CRUs: in a) extensor digitorum longus (EDL) muscles from 2 years old mice, either sedentary or trained for 1 year in wheel cages; and b) denervated EDL muscles from adult mice and rats. We analyzed muscle samples using a combination of structural (confocal and electron microscopy), biochemical (assessment of oxidative stress via western blot), and functional ( ex-vivo contractile properties and mitochondrial Ca 2+ uptake) experimental procedures. The results collected in structural studies indicates that: a) ageing and denervation result in partial uncoupling between mitochondria and CRUs; b) exercise and re-innervation either maintains (in old mice) or restores (in transiently denervated rats) the association between the two organelles. Functional studies supported the hypothesis that CRU-mitochondria coupling is important for mitochondrial Ca 2+ uptake, optimal force generation, and muscle performance. Taken together, our results indicate that muscle activity maintains/improves proper association between CRUs and mitochondria.