Antioxidants improve the phenotypes of dilated cardiomyopathy and muscle fatigue in mitochondrial superoxide dismutase-deficient mice

Abstract

Redox imbalance elevates the reactive oxygen species (ROS) level in cells and promotes age-related diseases. Superoxide dismutases (SODs) are antioxidative enzymes that catalyze the degradation of ROS. There are three SOD isoforms: SOD1/CuZn-SOD, SOD2/Mn-SOD, and SOD3/EC-SOD. SOD2, which is localized in the mitochondria, is an essential enzyme required for mouse survival, and systemic knockout causes neonatal lethality in mice. To investigate the physiological function of SOD2 in adult mice, we generated a conditional Sod2 knockout mouse using a Cre-loxP system. When Sod2 was specifically deleted in the heart and muscle, all mice exhibited dilated cardiomyopathy (DCM) and died by six months of age. On the other hand, when Sod2 was specifically deleted in the skeletal muscle, mice showed severe exercise disturbance without morphological abnormalities. These provide useful model of DCM and muscle fatigue. In this review, we summarize the impact of antioxidants, which were able to regulate mitochondrial superoxide generation and improve the phenotypes of the DCM and the muscle fatigue in mice.

Figure 1

Heart and muscle-specific Mn-SOD-deficient mice. (A) Cre recombinase is expressed under the control of a heart and muscle-specific muscle creatine kinase (MCK) promoter. Cre recombinase recombines the loxP sites selectively to generate heart and muscle-specific Mn-SOD-deficient mice; (B) Isolated hearts from a H/M-Sod2^−/− mouse (top left) and a littermate control mouse (top right) at eight weeks of age. EUK-8 treatment improved the enlarged heart of a H/M-Sod2^−/− mouse (bottom left).

Figure 2

The chemical structures of the antioxidants described in this review. (A) EUK-8; (B) MnTBAP; (C) MnM2Py₂P; (D) MnM2Py₂P, and (E) procyanidins.

Figure 3

Muscle-specific Mn-SOD-deficient mice. (A) Cre recombinase is expressed under the control of a skeletal muscle-specific human skeletal actin (HSA) promoter. Cre recombinase recombines the loxP sites selectively to generate muscle-specific Mn-SOD-deficient mice; (B) Sections of gastrocnemius (Gastro) and tibialis anterior (TA) muscles from control mice (left panels) and muscle-Sod2^−/− mice (right panels). Examples of HE staining (top panels) and enzymatic staining for succinate dehydrogenase (SDH, middle panels) and cytochrome c oxidase activity (COX, bottom panels) are shown.