Nutmeg Extract Increases Skeletal Muscle Mass in Aging Rats Partly via IGF1-AKT-mTOR Pathway and Inhibition of Autophagy

Figure 5

Proposed scheme of nutmeg action in soleus muscle. Activation of phosphatidylinositol 3-kinase (PI3K) pathway can promote skeletal muscle hypertrophy and increase skeletal muscle mass. This pathway’s effect on skeletal muscle has implicated most prominently downstream of IGF1 signalling. IGF1 can lead to muscle hypertrophy coming predominantly through its ability to activate the PI3K/AKT signalling pathway. AKT is a serine-threonine protein kinase that can induce protein synthesis by activating mTOR and its downstream effectors. The kinase mTOR interacts with several proteins to form two complexes mTORC1 and mTORC2 that leads to protein synthesis. AKT blocks key mediators of skeletal muscle atrophy transcriptional factor and ubiquitin ligases, thereby inhibiting nuclear translocation of the FoxO. Once phosphorylated by AKT, the FoxOs are excluded from the nucleus, and upregulation of MuRF1 and MAFbx is blocked so it leads to inhibiting protein degradation. Inhibition FoxO also leads to expression autophagy-related genes such as LC3 and thereby the autophagy process also decreased by inhibition of FoxO. The IGF1-AKT-mTOR pathway plays crucial role in muscle mass and function maintenance and also among elderly and can be also one of the potential targets of sarcopenia treatment. Macelignan found in nutmeg extract is already known to have PPAR-γ agonist effect. From previous in vitro study, nutmeg extract shows positive effects toward insulin sensitivity and glucose metabolism. Nutmeg extract may also have another activity that modulates phosphatidylinositol 3-kinase (PI3K) that can induce skeletal muscle hypertrophy or at least preserve muscle mass through protein synthesis via IGF1-AKT-mTOR pathway.