Improper Remodeling of Organelles Deputed to Ca2+ Handling and Aerobic ATP Production Underlies Muscle Dysfunction in Ageing

Abstract

Proper skeletal muscle function is controlled by intracellular Ca2+ concentration and by efficient production of energy (ATP), which, in turn, depend on: (a) the release and re-uptake of Ca2+ from sarcoplasmic-reticulum (SR) during excitation–contraction (EC) coupling, which controls the contraction and relaxation of sarcomeres; (b) the uptake of Ca2+ into the mitochondrial matrix, which stimulates aerobic ATP production; and finally (c) the entry of Ca2+ from the extracellular space via store-operated Ca2+ entry (SOCE), a mechanism that is important to limit/delay muscle fatigue. Abnormalities in Ca2+ handling underlie many physio-pathological conditions, including dysfunction in ageing. The specific focus of this review is to discuss the importance of the proper architecture of organelles and membrane systems involved in the mechanisms introduced above for the correct skeletal muscle function. We reviewed the existing literature about EC coupling, mitochondrial Ca2+ uptake, SOCE and about the structural membranes and organelles deputed to those functions and Finally, we summarized the data collected in different, but complementary, projects studying changes caused by denervation and ageing to the structure and positioning of those organelles: a. denervation of muscle fibers—an event that contributes, to some degree, to muscle loss in ageing (known as sarcopenia)—causes misplacement and damage: (i) of membrane structures involved in EC coupling (calcium release units, CRUs) and (ii) of the mitochondrial network; b. sedentary ageing causes partial disarray/damage of CRUs and of calcium entry units (CEUs, structures involved in SOCE) and loss/misplacement of mitochondria; c. functional electrical stimulation (FES) and regular exercise promote the rescue/maintenance of the proper architecture of CRUs, CEUs, and of mitochondria in both denervation and ageing. All these structural changes were accompanied by related functional changes, i.e., loss/decay in function caused by denervation and ageing, and improved function following FES or exercise. These data suggest that the integrity and proper disposition of intracellular organelles deputed to Ca2+ handling and aerobic generation of ATP is challenged by inactivity (or reduced activity); modifications in the architecture of these intracellular membrane systems may contribute to muscle dysfunction in ageing and sarcopenia.

Ageing Causes Ultrastructural Modification to Calcium Release Units and Mitochondria in Cardiomyocytes

“…In this manuscript, we have taken advantage of the previous experience collected studying skeletal [40][41][42]54,55] and cardiac [8][9][10]34,59] muscle to study CRUs and mitochondria and their intracellular disposition, in ageing hearts from mice. The results presented in this manuscript show that ageing in cardiomyocytes causes the following:…”

“…In physiological conditions, though, the synchronous activation of many sparks induced by depolarization, each of them arising from a different CRU, generates a homogeneous transient that leads to uniform activation of the contractile machinery [77][78][79]. However, the structural disruption of this system in ageing could result in improper activation of the contractile machinery [52][53][54].…”

“…In the past 10 years, we have investigated age-related changes in CRUs and mitochondria in skeletal muscle fibers [54]. Sedentary ageing causes (a) decrease in the number of sites available for Ca 2+ release (i.e., the CRUs) [40,41], (b) decreased number and volume of mitochondria [41,42], and (c) alterations in the intracellular disposition and orientation of CRUs and mitochondria with respect to striation of myofibrils [41,42].…”

Musculoskeletal Aging and Sarcopenia in the Elderly

“…Through the measurement of the plasma concentration of a large protein array, the authors identified a proteomic signature of muscle mitochondrial function assayed by phosphorous magnetic resonance spectroscopy [ 2 ]. The relevance of mitochondrial dysfunction to sarcopenia is further highlighted by the observation that alterations in intracellular calcium handling impact mitochondrial bioenergetics [ 3 ]. Muscle fiber denervation, an event involved in the pathogenesis of sarcopenia, induces damage of membrane structures involved in calcium handling and excitation–contraction coupling, and disruption of the mitochondrial network [ 3 ].…”

“…The relevance of mitochondrial dysfunction to sarcopenia is further highlighted by the observation that alterations in intracellular calcium handling impact mitochondrial bioenergetics [ 3 ]. Muscle fiber denervation, an event involved in the pathogenesis of sarcopenia, induces damage of membrane structures involved in calcium handling and excitation–contraction coupling, and disruption of the mitochondrial network [ 3 ]. These alterations were also described in physically inactive old mice and were rescued by electrical stimulation regular exercise in both rodents and older persons [ 3 ].…”