Exercise Protects Skeletal Muscle Fibers from Age-Related Dysfunctional Remodeling of Mitochondrial Network and Sarcotubular System

In skeletal muscles fibers, cellular respiration, excitation-contraction (EC) coupling (the mechanism that translates action potentials in Ca²⁺ release), and store-operated Ca²⁺ entry (SOCE, a mechanism that allows recovery of external Ca²⁺ during fatigue) take place in organelles specifically dedicated to each function: (a) aerobic ATP production in <i>mitochondria</i>; (b) EC coupling in intracellular junctions formed by association between transverse tubules (TTs) and sarcoplasmic reticulum (SR) named <i>triads</i>; (c) SOCE in <i>Ca</i>²⁺<i>entry units</i> (CEUs), SR-TT junctions that are in continuity with membranes of triads, but that contain a different molecular machinery (see Graphical Abstract). In the past 20 years, we have studied skeletal muscle fibers by collecting biopsies from humans and isolating muscles from animal models (mouse, rat, rabbit) under different conditions of muscle inactivity (sedentary aging, denervation, immobilization by casting) and after exercise, either after voluntary training in humans (running, biking, etc.) or in mice kept in wheel cages or after running protocols on a treadmill. In all these studies, we have assessed the ultrastructure of the mitochondrial network and of the sarcotubular system (i.e., SR plus TTs) by electron microscopy (EM) and then collected functional data correlating (i) the changes occurring with aging and inactivity with a loss-of-function, and (ii) the structural improvement/rescue after exercise with a gain-of-function. The picture that emerged from this long journey points to the importance of the internal architecture of muscle fibers for their capability to function properly. Indeed, we discovered how the intracellular organization of the mitochondrial network and of the membrane systems involved in controlling intracellular calcium concentration (i[Ca²⁺]) is finely controlled and remodeled by inactivity and exercise. In this manuscript, we give an integrated picture of changes caused by inactivity and exercise and how they may affect muscle function.