Novel Intriguing Strategies Attenuating to Sarcopenia

Figure 1

Myostatin signals through the ActRIIB-ALK4/5 heterodimer activate Smad2/3 with blocking of MyoD transactivation in an autoregulatory feedback loop. In addition, Smad3 sequesters MyoD in the cytoplasm to prevent it from entering the nucleus and activating the stem cell population. Recent findings [105, 106] have suggested that myostatin-Smad pathway inhibits protein synthesis probably due to blocking the functional role of Akt. Supplementation with ursolic acid upregulates the amount of IGF-I and insulin and then stimulates protein synthesis by activating Akt/mTOR/p70S6K pathway [29]. Treatment with ACE inhibitor also enhances IGF-I level in muscle. Amino acid supplementation enhances protein synthesis by stimulating mTOR [107]. Akt blocks the nuclear translocation of FOXO to inhibit the expression of Atrogin-1 and MuRF1 and the consequent protein degradation. Proteasome inhibitors combat the ubiquitin-proteasome signaling activated by these atrogenes. In cachexic muscle, supplementation with EPA downregulates the amount of TNF-α and NF-κB [63, 64]. Endurance exercise increases the amount of PGC-1α through calcineurin- or CaMK-dependent signaling [108]. Both activated PGC-1α, and cyclophilin inhibitor protects several mitochondrial disorders (apoptosis, oxidative damage, etc.) elicited by the increase in NF-κB and Bax and/or the decrease in Bcl-2 in senescent muscle. ACE; angiotensin-converting enzyme, ActRIIB; activin receptor IIB, ALK4/5; activin-like kinase 4/5, CaMK; calmodulin kinase, eIF4E; eukaryotic initiation factor 4E, EPA; eicosapentaenoic acid, FOXO; Forkhead box O, IGF-I; insulin-like growth factor-I, IKK; inhibitor of κB kinase, mTOR; mammalian target of rapamycin, MuRF1; muscle ring-finger protein 1, NF-κB; nuclear factor of kappa B, PGC-1α; peroxisome proliferator-activated receptor γ coactivator α, PI3-K; phosphatidylinositol 3-kinase, Rheb; Ras homolog enriched in brain, TNF-α; tumor nectosis factor-α, TORC1; a component of TOR-signaling complex 1.