Updated publication reference for PubMed record(s): 29719249. Protein aggregates and cytoplasmic vacuolization are major hallmarks of multisystem proteinopathies (MSP) that lead to muscle weakness. Here, we identify METTL21C as a novel skeletal muscle-specific lysine methyltransferase. Insertion of a -galactosidase cassette into the Mettl21c mouse locus revealed METTL21C is specifically expressed in MYH7 positive skeletal muscle fibers. Ablation of the Mettl21c gene reduced endurance capacity and led to accumulation of cellular residuals due to incomplete autophagy in the skeletal muscle of Mettl21c-/- mutants during aging. Moreover, denervation-induced muscle atrophy highlighted further impairments of autophagy-related proteins, including LC3, p62, and cathepsins in Mettl21c-/- muscles. In addition, we demonstrate METTL21C interacts with the ATPase p97 (VCP), which is mutated in various human MSP conditions. We also reveal METTL21C trimethylates p97 on Lys315 residue, and found loss of this modification reduced p97 hexamer formation and ATPase activity in vivo. We conclude the methyltransferase METTL21C is an important modulator of protein degradation in skeletal muscle under both normal and enhanced protein breakdown conditions due to its ability to trimethylate and regulate p97.