# Physical Activity and Redox Balance in the Elderly: Signal Transduction Mechanisms
## 4 Insights into Signal Transduction
### Skeletal and Cardiac Muscle  
The importance of Nrf2 has also been evidenced in muscle. In fact, [PERSON] et al. (2019) [67] showed that the level of Nrf2 mRNA in skeletal muscle decreases with aging, and concomitantly, a frailty phenotype arises. Muscle function and mass are similar in young wild-type and young Nrf2-_null_ mice. In middle-aged and old Nrf2-_null_ mice, muscle function significantly decreases with enhancement of frailty in old Nrf2-_null_ mice [67]. This phenotype hinges on a decrease of mitochondrial biogenesis and alteration of mitochondrial morphology in skeletal muscle. In skeletal muscle, other pathways also seem to be involved in redox-balance signalling. In fact, skeletal muscle is a primary source of ROS during exercise, because during muscle contraction, there is a massive production of superoxide radical (O\({}_{2}\)\({}^{-}\)) [67]. In rats, a combination of antioxidants (such as resveratrol) and exercise significantly increases muscle mass and grip strength in sarcopenia old mice, and reduces abnormal sarcomere length [68]. Concomitantly, the authors observed a significant increase in the levels of the phosphorylated form of 5\({}^{\prime}\) AMP-activated protein Kinase (pAMPK) and of Sirttuin1 (Sirt1), suggesting the involvement of the AMPK/Sirt1 pathway [68]. This last pathway is also involved in AdipoRon function that is used to reduce oxidative stress and inflammation in dystrophic mice [69]. AdipoRon increases the levels of pAMPK that reduces NF-Kb and increases the dystrophin analogue utrophin [69]. AdipoRon also increases muscle strength and endurance, leading to better physical performance [69]. The antioxidant and antiagging effects of resveratrol have been studied also in the kidney [70]. In particular, the authors suggest that resveratrol can activate both Nrf2 and AMPK/sirtuin1 pathways in the kidney, to counteract the pathologic aging effect in this organ. In fact, transfection with Nrf2 and SIRT1 siRNAs in HK2 cells blocks the antioxidant effect of resveratrol [70]. The Akt signal-transduction pathway has been evidenced in skeletal muscle, in association with exercise and redox balance. For example, in mice, swimming exercise reduces ROS, and prevents high-fat diet-induced insulin resistance through the decrease of NADPH oxidase 4 (Nox4), as well as the increase of Akt signal transduction in skeletal muscle [71]. Akt signalling is also required for the correct regulation of muscle stem-cell (MuSCs) homeostasis during aging. In fact, [PERSON] et al. (2019) [72] found WNT1-Inducible Signalling Pathway Protein 1 (WISP1) as a fibro-adipogenic progenitor protein that is strongly downregulated during aging. This protein is important for muscle regeneration and the asymmetric division of muscle stem cells through Akt signalling. In fact, systemic treatment of aged mice with WISP1 restores the proliferation and differentiation of aged muscle stem cells [72]. Peroxisome Proliferator-Activated Receptor gamma (PPAR-gamma) and Peroxisome proliferatorator-activated receptor Gamma Coactivator-1 alpha (PGC1-alpha) have been proposed as important players in muscle remodelling induced by exercise through MitogenActivated Protein Kinases (MAPKinases), and are also correlated with redox balance. In particular, p38 MAPKinase activates PPAR-gamma. Sirt1, in turn, depending on physical exercise, activates PGC1-alpha [73]. PGC1-alpha is implicated in aging-associated mitochondrial diseases dysregulateding ROS production and mitochondrial network structure in skeletal muscle, during aging and exercise training. PGC1-alpha is also activated by ROS through NF-kB, AMPK, and finally, by nitric oxide (NO) produced during muscle contraction [73; 74]. PGC1-alpha-_null_ aged mice show lower running endurance, higher mitochondrial damage, increased ROS and higher oxidative stress than do young mice. Exercise training increases maximal respiratory capacity, both in PGC1-alpha-_null_ and wild-type mice. Instead, the rescue of mitochondrial homeostasis occurs in a PGC1-alpha-dependent manner [74].