Pifithrin-µ increases mitochondrial COX biogenesis and MnSOD activity in skeletal muscle of middle-aged mice.

ABSTRACT

We investigated the biogenesis and mitochondrial antioxidant capacity of cytochrome c oxidase (COX) within the skeletal muscle under the treatments of p53 inhibitors (pifithrin, PFTα and PFTµ). Significantly, PFTµ increased mtDNA content and COX biogenesis. These changes coincided with increases in the activity and expression of manganese superoxide dismutase (MnSOD), the key antioxidant enzyme in mitochondria. Conversely, PFTα caused muscle loss, increased oxidative damage and decreased MnSOD activity in intermyofibrillar (IMF) mitochondria. Mechanically, PFTµ inhibited p53 translocation to mitochondria and thus increased its transcriptional activity for expression of synthesis of cytochrome c oxidase 2 (SCO2), an important assembly protein for COX. This study provides in vivo evidence that PFTµ, superior to PFTα, preserves muscle mass and increases mitochondrial antioxidant activity.