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

Pietrangelo, Laura, Michelucci, Antonio, Ambrogini, Patrizia, Sartini, Stefano, Guarnier, Flavia A., Fusella, Aurora, Zamparo, Ilaria, Mammucari, Cristina, Protasi, Feliciano, Boncompagni, Simona
Archives of biochemistry and biophysics 2019 v.663 pp. 22-33
Western blotting, adults, calcium, calcium signaling, electron microscopy, exercise, mice, mitochondria, muscles, oxidative stress, rats
In fast-twitch fibers from adult mice Ca2+ 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 Ca2+ 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 Ca2+ uptake) experimental procedures. The results collected in structural studies indicate that: a) ageing and denervation result in partial uncoupling between mitochondria and CRUs; b) exercise 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 Ca2+ uptake, optimal force generation, and muscle performance. Taken together our results indicate that muscle activity maintains/improves proper association between CRUs and mitochondria.