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

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.

► PFTμ improved mitochondrial biogenesis in skeletal muscle of middle-aged mice. ► PFTμ increased SOD expressions and MnSOD activity in skeletal muscle. ► PFTα impaired the assembly of COX in skeletal muscle by decreasing SCO proteins. ► PFTμ is superior to PFTα for its ability to preserve muscle mass. ► p53 mitochondrial translocation may be harmful to mitochondrial function.