## 6 Implications and Perspectives  
Our data suggest that the benefits of exercise would also be reduced in _Sparc_ KO mice, not only because some of exercise benefits are directly mediated via SPARC, but also because physical performance and muscle performance is reduced as a result of _Sparc_ KO (indirect effects). As an illustration, _Sparc_ KO increases tumor growth [120; 121], loss of SPARC increases cancer progression [122] and the tumorigenesis is prevented and suppressed by exercise-induced SPARC [8; 123; 124]. More generally, since SPARC is also a myokine secreted during exercise [2; 8], exercise benefits including metabolic benefits and inflammation regulation would also be reduced with the _Sparc_ KO since SPARC has been shown to play roles in metabolism [44], inflammation regulation [47] and cancer homeostasis [46]. Thus, its absence from circulation would impact tissues other than the SM. For instance, even some of the mechanisms underlying the beneficial effects of exercise that have been shown to involve factors other than SPARC, such as tumor growth suppression through interleukin 6 and epinephrine [92], would also be deficient in _Sparc_ KO mice, since the absence of SPARC would reduce the ability of SM to correctly secrete the other myokines involved in the related pathways. Overall, SM, both as a secretory organ [2] and a metabolic engine, represents the key tissue upon which exercise benefits depend. SPARC represents a \"booster\" of the SM, with beneficial effects on some other tissues as well. Therefore, SPARC and the pathways it governs would represent good targets to pharmacologically mimic the effects of SPARC, including improved muscle strength and metabolic performances. This is of a particular importance for individuals suffering from health problems, such as heart failure or physical handicap and, therefore, are unable to perform the required physical activity although they need it (reduce obesity, treat lipid disorders, etc.). In such a scenario we could imagine an \"exercise pill\", targeting SPARC-related pathways and inducing exercise-like effects that would also be of a high therapeutic importance for diseases, such as sarcopenia. Such a therapeutic goal still requires further investigations into the implications of SPARC, not only within the SM but also on other tissues and in the diverse aspects of homeostasis. This will both extend the expected benefits of such an \"exercise pill\" and anticipate the side effects to decide whether it would be better given as a systemic drug or rather target a specific tissue (that would be the SM based on this study) to optimize clinical efficiency. Importantly, the results obtained from studying SPARC/_Sparc_ in mice would be expected to be valid in humans, due the high homology between mouse and human SPARC [104], which would reduce the bridge between results in animals and future clinical studies. Perspectives of the future studies on SPARC implications in SM metabolism and contractile properties, both for sedentary and exercise individuals, would be of great clinical importance not only for SM diseases but also for ageing-related health deterioration and, due to the importance of the SM in the energy homeostasis, energy balance-related pathologies such as obesity and diabetes. Our study was conducted only on male mice. Therefore, we acknowledge the limitation of sex-determined factors. Similar studies in female subjects, as well as studies comparing male and female subjects, will add significant data of clinical importance, especially with the sex-related difference effects on SM and exercise patterns, such as exercise capacity [125], pinch force reproduction [126], maximal oxygen uptake [127], cardiac adaptation to exercise [125], as well as metabolism, including lactate levels [128; 129], aerobic oxidation and anaerobic glycolysis [130].