From Initiation to Elongation: <scp>eIF3</scp> as a Dual‐Phase Guardian of Mitochondrial Integrity and Protein Homeostasis in Skeletal Muscle

Skeletal muscle is the largest organ by mass in the human body, and its functional capacity depends on the precise coordination of protein synthesis, mitochondrial bioenergetics, and regenerative potential. Eukaryotic translation initiation factor 3 (eIF3), a 13-subunit complex (~800 kDa) best known for its multifaceted roles in cancer, is now emerging as a key translational regulator in skeletal muscle physiology and disease. Here, we present a perspective that synthesizes recent advances into a unifying "dual-phase guardian" model. In the first phase, eIF3f acts at the level of translation initiation as a scaffold bridging mTORC1 and S6K1, integrating anabolic and catabolic signals, particularly the MAFbx/Atrogin-1 ubiquitin-proteasome axis, to govern net protein synthesis and muscle mass. In the second phase, eIF3e remains bound to 80S ribosomes during early translation elongation (codons 1-60) of approximately 2700 mRNAs encoding mitochondrial and membrane-associated proteins, facilitating co-translational quality control through chaperone recruitment (e.g., CCT/TRiC). Haploinsufficiency of eIF3e in mice produces mitochondrial hyperfusion, diminished respiratory complex I activity, sarcomeric degeneration, and progressive loss of grip strength, a phenotype recapitulating features of mitochondrial myopathy. Complementing these findings, eIF3b supports satellite cell-mediated muscle regeneration by resolving RNA G-quadruplex structures in the 5'-UTR of Anp32e mRNA, while eIF3a modulates fibrotic remodeling through TGF-β/Smad3 signaling. We situate these subunit-level findings within the broader landscape of translational regulators in muscle (eIF2α/ISR, eIF5A, eEF2) and critically evaluate the translational potential and therapeutic challenges, including the absence of human clinical data, tissue-selectivity concerns, and species-specific limitations, that must be addressed before these mechanistic insights can inform treatment of sarcopenia, disuse atrophy, and mitochondrial myopathy.