(VP115) THE MITOPHAGY RECEPTOR NIX COORDINATES NUCLEAR CALCIUM SIGNALING TO MODULATE THE MUSCLE PHENOTYPE.

Background:

Background: Mitochondrial quality control is critical in muscle to ensure both contractile and metabolic function. Homeostatic pathways operate to ensure mitochondrial health by coordinating mitochondrial biogenesis with the removal of damaged mitochondrial components, which have been collectively termed mitochondrial quality control. In addition, mitochondria can respond to cell stress by integrating signaling pathways that orchestrate a tissue level response, but the mechanisms for this are largely unknown. Nix is a BCL-2 family member, mitophagy receptor, and has recently been implicated in muscle atrophy and aging. In human and rodent myotubes, we previously demonstrated that Nix orchestrates both mitochondrial calcium and mTOR signaling in responsive to a lipotoxic stress leading mitochondrial turnover and impaired insulin signaling. In addition, human GWAS suggests altered Nix expression could predispose individuals to manifestations of mitochondrial disease.

METHODS AND RESULTS: METHODS/

Results: To understand the role of Nix in skeletal muscle, we generated a muscle-specific Nix knockout model. Nix knockout mice displayed a ragged-red fibre phenotype, which was more evident in male mice, along with accumulation of senescent mitochondria and sarcoplasmic reticulum. Intriguingly, Nix knockout mice were more insulin sensitive with a corresponding increase in glycogen-rich muscle fibres. Kinome- and gene expression analyses revealed that Nix knockout impairs NFAT and canonical myostatin signaling, with alterations in muscle fibre-type composition and evidence of regeneration. Soleus muscle displayed reduced myoglobin, MYH2, and TNNT1 expression, along with increased in MYH4. Finally, mechanistic experiments in C2C12 myotubes demonstrated that Nix expression increased during differentiation and following electrical pacing in parallel with PGC-1, and is both necessary and sufficient to modulate mitophagy, nuclear calcium signaling, and gene expression.

Conclusion:

Conclusion: Collectively, these observations indicate that in addition to a role in cell death and mitophagy, Nix maintains sarcoplasmic reticulum and calcium homeostasis, and modulates the oxidative muscle phenotype. These observations help explain how mitochondrial quality control pathways can modulate tissue homeostasis in response to stress and metabolic disease.