Stouth 2023 Autophagy

Stouth DW, vanLieshout TL, Mikhail AI, Ng SY, Raziee R, Edgett BA, Vasam G, Webb EK, Gilotra KS, Markou M, Pineda HC, Bettencourt-Mora BG, Noor H, Moll Z, Bittner ME, Gurd BJ, Menzies KJ, Ljubicic V (2023) CARM1 drives mitophagy and autophagy flux during fasting-induced skeletal muscle atrophy. https://doi.org/10.1080/15548627.2023.2288528

» Autophagy [Epub ahead of print]. PMID: 38018843 Open Access

Stouth Derek W, vanLieshout Tiffany L, Mikhail Andrew I, Ng Sean Y, Raziee Rozhin, Edgett Brittany A, Vasam Goutham, Webb Erin K, Gilotra Kevin S, Markou Matthew, Pineda Hannah C, Bettencourt-Mora Brianna G, Noor Haleema, Moll Zachary, Bittner Megan E, Gurd Brendon J, Menzies Keir J, Ljubicic Vladimir (2023) Autophagy

Abstract: CARM1 (coactivator associated arginine methyltransferase 1) has recently emerged as a powerful regulator of skeletal muscle biology. However, the molecular mechanisms by which the methyltransferase remodels muscle remain to be fully understood. In this study, carm1 skeletal muscle-specific knockout (mKO) mice exhibited lower muscle mass with dysregulated macroautophagic/autophagic and atrophic signaling, including depressed AMP-activated protein kinase (AMPK) site-specific phosphorylation of ULK1 (unc-51 like autophagy activating kinase 1; Ser555) and FOXO3 (forkhead box O3; Ser588), as well as MTOR (mechanistic target of rapamycin kinase)-induced inhibition of ULK1 (Ser757), along with AKT/protein kinase B site-specific suppression of FOXO1 (Ser256) and FOXO3 (Ser253). In addition to lower mitophagy and autophagy flux in skeletal muscle, carm1 mKO led to increased mitochondrial PRKN/parkin accumulation, which suggests that CARM1 is required for basal mitochondrial turnover and autophagic clearance. carm1 deletion also elicited PPARGC1A (PPARG coactivator 1 alpha) activity and a slower, more oxidative muscle phenotype. As such, these carm1 mKO-evoked adaptations disrupted mitophagy and autophagy induction during food deprivation and collectively served to mitigate fasting-induced muscle atrophy. Furthermore, at the threshold of muscle atrophy during food deprivation experiments in humans, skeletal muscle CARM1 activity decreased similarly to our observations in mice, and was accompanied by site-specific activation of ULK1 (Ser757), highlighting the translational impact of the methyltransferase in human skeletal muscle. Taken together, our results indicate that CARM1 governs mitophagic, autophagic, and atrophic processes fundamental to the maintenance and remodeling of muscle mass. Targeting the enzyme may provide new therapeutic approaches for mitigating skeletal muscle atrophy. • Keywords: Atrophy, Autophagy, Coactivator-associated arginine methyltransferase 1, Fasting, Mitophagy, Skeletal muscle • Bioblast editor: Plangger M

Labels: MiParea: Respiration, Genetic knockout;overexpression 

Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue 

Coupling state: LEAK, OXPHOS  Pathway: N, NS  HRR: Oxygraph-2k, O2k-Fluorometer 

2023-12, AmR