Intermittent TORC1 inhibition combined with transient acetyl-CoA elevation can recreate the germline mtDNA quality‑control cycle in skeletal muscle. The germline maintains mitochondrial fidelity through two sequential steps: (1) a mtDNA bottleneck that amplifies heteroplasmy variance, and (2) programmed germline mitophagy (PGM) that eliminates defective organelles via BNIP3‑dependent autophagy when TORC1 is suppressed at meiosis entry. Somatic muscle lacks both mechanisms, allowing deleterious mtDNA mutations to accumulate and impair β‑oxidation, a deficit exacerbated by reduced L‑carnitine‑mediated fatty‑acid import and dysregulated carnitine acetyltransferase (CrAT) activity. Recent work shows that pre‑binding of CoA or acetyl‑CoA inhibits CrAT catalysis ~100‑fold through a conformational shift, suggesting that acute rises in acetyl‑CoA could transiently suppress CrAT flux and signal metabolic stress.
We hypothesize that pulsatile elevation of acetyl‑CoA (via short‑term sodium acetate administration) during periods of TORC1 inhibition (using low‑dose rapamycin) will mimic the germline’s variance‑amplification and selective purge in aged skeletal muscle. Specifically, acetyl‑CoA‑mediated CrAT inhibition will reduce acetyl‑CoA consumption, raising the acetyl‑CoA/CoA ratio and activating AMPK, which in turn upregulates BNIP3 and drives mitophagy independently of the PINK1/Parkin pathway. This surge in BNIP3‑dependent autophagy will preferentially remove mitochondria bearing high mutational loads, because the preceding bottleneck‑like effect of reduced CrAT activity lowers m
