trans-Cinnamaldehyde stimulates mitochondrial biogenesis through PGC-1α and PPARβ/δ leading to enhanced GLUT4 expression

Working hypotheses of CA mechanism of myotube PGC-1α induction leading to increased GLUT4 content. Under conditions of normal glucose content, (1) CA enters the cell and inhibits mitochondrial oxidative metabolism (through an unknown mechanism) leading to decreased ATP content. Reduced ATP content stimulates AMPK (2) leading to the activation and phosphorylation of PGC-1α and other downstream targets including PPARα and PPARβ/δ, promoting PGC-1α, PPAR, and SIRT1 expression (3). Increased PGC-1α expression leads to heightened MEF2 expression (4) and ultimately increased GLUT4 content (5). Increased PGC-1α expression also stimulates mitochondrial biogenesis (6). Increased PPARβ/δ activation leads to heightened expression of SIRT1 leading to enhanced PGC-1α activation (7). And (8), increased GLUT4 content may ultimately increase glucose uptake stabilizing cellular ATP content/energetics (although these hypotheses require further experimental validation).223