## 5 Conclusions and Hypothetical Mechanisms  
_Sparc_ KO effects are toward a reduced body and WAT weights with a negative SM phenotype (metabolism and strength). Such negative effects worsen with ageing but relatively improve through exercise (Figure 2). While exercise reduces risk factor for many diseases, ageing increases those risks [108]. Within this context, [PERSON] et al. reported 24 genes (including _SPARC_) that are both upregulated by exercise and downregulated by ageing [8] suggesting, once more, that some of the exercise-induced benefits such as mitochondrial biogenesis [109] could be SPARC-dependent or partially mediated by SPARC. It is within this perspective that we developed our hypothesis. The exercise-produced lactate induces both an up-regulation of the expression of the cytochrome oxidase gene and protein, as well as a mitochondrial biogenesis activation signal [79], and since _Sparc_ KO did not induce any genotype effect on the different lactate levels we measured (both WT and _Sparc_ KO mice had statistically similar lactate levels) but reduced the expression of the MT-CO1 (WT and _Sparc_ KO mice have similar lactate levels but WT mice express more MT-CO1 than _Sparc_ KO mice), we hypothesize that the exercise-produced lactate-induced cytochrome oxidase upregulation and mitochondrial biogenesis activation do require SPARC (Figure 3A). This would, at least in part,  
Figure 2: SPARC-deficiency impacts. Our data highlight that _Sparc_ KO effects are toward a reduced body and white adipose tissue weights with a negative skeletal muscle phenotype (metabolic and strength). Such negative effects worsen with ageing but relatively improve through exercise. Abbreviations: KO, knockout; SPARC, secreted protein acidic and rich in cysteine. explain why SPARC deficiency reduces tumor growth. Indeed, cancer cells require glycolytic energy and produce lactate, leading to lower pH, compared to normal tissue extracellular pH [110; 111], and lactate would be an attempt to increase oxidative phosphorylation capacity via improving mitochondrial biogenesis. However, in the absence of SPARC this lactate-induced mitochondrial biogenesis remains limited, which worsens the tumor bioenvironment and results in tumor progress inhibition. This concept of lactate-related signaling correlates with the theory presenting lactate as a signaling molecule \"lactormone\" in the context of lactate shuttle [112; 113] of lactate formation, utilization and exchange between tissues [114]. The results of Figure 1B further support our hypothesis that SPARC-dependent exercise impacts SM. Indeed, whereas there is a significant effect of exercise (increase in COL1A1 expression) in WT mice (WT-Ex > WT-Sed), there is no such effect in _Sparc_ KO mice (both KO-Ex and KO-Sed mice have statistically similar expression of COL1A1). This also correlates with the genotype-induced decrease in COL1A1 expression (WT > KO) although both WT and _Sparc_ KO mice had equal amounts of exercise (as detailed in the introduction of Section 4), therefore, indicating that exercise-induced COL1A1 is SPARC-dependent (Figure 3A). Moreover, since exercise-induced COL1A1 seems SPARC-dependent, and based on the importance of collagens in the SM structure (and fibrillar collagen I is reported to bind SPARC [115]) and development [116], this could also explain, in part, the low tibialis anterior muscle weight in _Sparc_ KO mice compared to WT mice, even though all mice had similar amounts of exercise. Thus, this also suggests that SM development (tibialis anterior weight percentage increase; Table 3), as a part to the adaptation to exercise, would also be SPARC-dependent (Figure 3A). Figure 3: Hypothetical mechanisms linking SPARC to the exercise-induced SPARC-mediated changes in the skeletal muscle phenotype. **[A]** Exercise induces the secretion and expression of SPARC as well as the production of lactate.