## 2 SPARC: Metabolites and Homeostasis  
Both ECM and the proteins associated with it have the ability to interact between them as well as with cells, other active molecules, and cell receptors under diverse physiological and pathological conditions [28; 29; 30; 31]. The ECM and its associated proteins represent the frame into which cells reside and upon which key tissue properties depend. Indeed, what provides tissue with its nature (hard, soft, etc.) and properties is governed by the cellular adhesion of cells constituting that tissue and their interactions through the ECM and its associated proteins. This explains the need for ECM remodeling and changes to adapt to new physiological or pathological conditions [32]. Furthermore, the content in other elements like calcium does impact the tissue nature and illustrates this concept as well. For instance, bones are known to be of a hard nature, and this is due to their rich content in calcium. Within this context, SPARC binds to both hydroxyapatite and collagen in a bone matrix [13; 33; 34], which strengthens the bone hardness. Therefore, the bone content in both SPARC and calcium and the binding ability these two components have would govern the strength and hardness of bones depending on how strong the adhesion is between osteocytes, their ECM, hydroxyapatite, and ECM-associated proteins (SPARC in the current example). Regarding the energy metabolism pattern, the two components of energy balance are energy storage and energy expenditure. The storage is mainly in the form of lipids in adipocytes, whereas the energy expenditure is governed by the muscle's energy usage (both resting metabolic rate and physical activity). As we have described in a recent paper [15], the ability of certain cells like adipocytes to expend would depend on the ECM's \"rigidity\", which would--in part--depend upon SPARC expression. Indeed, due to the interaction between SPARC and collagen, a deficiency in SPARC (such as in a _Sparc_ knock-out organism) would reduce collagen maturity and weaken the ECM structure, thereby reducing the ECM rigidity. ECM rigidity is defined by how strong the adhesion is between ECM and its associated protein and whether this adhesion would limit the cellular expansion of these cells surrounded by such an \"elastic\" or a \"rigid\" ECM [15]. Following this line of thought, how rigid the ECM of adipocyte is would govern whether the adiposity's development would be towards hyperplasia or hypertrophy. Whereas adipocyte's expansion would result from an \"elastic\" ECM, a \"rigid\" ECM would limit such expansion and rather direct the adiposity's development towards hyperplasia [15]. This results in different forms of adiposity distribution, which is mainly towards either subcutaneous or visceral fat accumulation. These metabolic outcomes control the metabolic phenotype [35; 36; 37], as well as morphidities and pathological complications [38] seen among different individuals with obesity. Studies on SPARC highlight its numerous metabolic implications, including energy metabolism in the skeletal muscle [15] and adiposity control [39] (Figure 2). Regarding the impact that ECM has on muscles, studies conducted on elderly men have shown that endurance training increased the expression of gene coding for both ECM proteins and SPARC in the skeletal muscles, and also genes related to metabolic functions such as oxidative phosphorylation (OXPHOS) [40]. Such results show a potential implication of SPARC in exercise-induced metabolic benefits depending on how strongly the _Sparc_ gene is expressed or knocked-out as we have previously described [15]. Herein, the differential expression of genes related to the ECM indicates a potential role of the ECM (and eventually ECM-associated proteins such as SPARC) within the muscular metabolic performance seen after training compared to the baseline. In addition, there is a possible link between the ECM and the mitochondrial function [41], which reflects other possible metabolic implications.