Proper skeletal muscle function is controlled by intracellular Ca2+ levels and by efficient production of energy (ATP). In the last 15 years our laboratory collected the following results: a. Short-term (7-15 days) denervation of muscle fibers causes misplacement and damage of membrane structures involved in EC coupling (calcium release units, CRUs) and of the mitochondrial network;1 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. Re-innervation and regular exercise promote rescue/maintenance of the proper architecture of CRUs, CEUs, and 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 re-innervation and exercise. These data suggested that integrity and proper disposition of intracellular organelles deputed to Ca2+ handling and aerobic generation of ATP is challenged by inactivity (or reduced activity) and improved following recover of movements. To definitely test this hypothesis, we generated a model of short-term inactivity, and randomly assigned mice to two experimental groups: i) immobilized adult mice, in which inactivity is obtained for 6 days by unilateral immobilization of a hind limb; ii) rehabilitation group, in which mice underwent 15 days of treadmill running after the immobilization procedure. The results collected in this study indicate that: i) even short-term inactivity caused significant alterations to the membrane system and organelles previously discussed; and ii) 2 weeks rehabilitation rescued proper intracellular organization of CRUs, CEUs, and mitochondria. [ABSTRACT FROM AUTHOR]