PGAM5 interacts with and maintains BNIP3 to license cancer-associated muscle wasting.

ABSTRACT

Regressing the accelerated degradation of skeletal muscle protein is a significant goal for cancer cachexia management. Here, we show that genetic deletion of Pgam5 ameliorates skeletal muscle atrophy in various tumor-bearing mice. pgam5 ablation represses excessive myoblast mitophagy and effectively suppresses mitochondria meltdown and muscle wastage. Next, we define BNIP3 as a mitophagy receptor constitutively associating with PGAM5. bnip3 deletion restricts body weight loss and enhances the gastrocnemius mass index in the age- and tumor size-matched experiments. The NH2-terminal region of PGAM5 binds to the PEST motif-containing region of BNIP3 to dampen the ubiquitination and degradation of BNIP3 to maintain continuous mitophagy. Finally, we identify S100A9 as a pro-cachectic chemokine via activating AGER/RAGE. AGER deficiency or S100A9 inhibition restrains skeletal muscle loss by weakening the interaction between PGAM5 and BNIP3. In conclusion, the AGER-PGAM5-BNIP3 axis is a novel but common pathway in cancer-associated muscle wasting that can be targetable. Abbreviation AGER/RAGE advanced glycation end-product specific receptor; BA1 bafilomycin A1; BNIP3 BCL2 interacting protein 3; BNIP3L BCL2 interacting protein 3 like; Ckm-Cre creatinine kinase, muscle-specific Cre; CM conditioned medium; CON/CTRL control; CRC colorectal cancer; FUNDC1 FUN14 domain containing 1; MAP1LC3A/LC3A microtubule associated protein 1 light chain 3 alpha; PGAM5 PGAM family member 5, mitochondrial serine/threonine protein phosphatase; S100A9 S100 calcium binding protein A9; SQSTM1/p62 sequestosome 1; TOMM20 translocase of outer mitochondrial membrane 20; TIMM23 translocase of inner mitochondrial membrane 23; TSKO tissue-specific knockout; VDAC1 voltage dependent anion channel 1.