Abstract
A new direction for the treatment of skeletal myopathies, which are mainly caused by abnormal mitochondrial metabolism, is the application of drugs and active substances to relieve oxidative stress in mitochondria. Phloretin, a dihydrochalcone active substance widely present in succulent fruits, has attracted attention for its strong antioxidant activity. This study aimed to investigate the potential antioxidant effects of phloretin and its potential mechanism of action in C2C12 mouse myoblasts. Under oxidative stress caused by 500 μmol/L H2O2, the addition of 10 μmol/L phloretin ameliorated the high level of reactive oxygen species, increased CuZn/Mn-dependent superoxide dismutase activities, and restored the loss of mitochondrial membrane potential. Additionally, apoptosis, necrocytosis, and the inhibition of cell proliferation caused by H2O2 stimulation were alleviated by phloretin. Moreover, phloretin significantly increased the expression of cyclin D1 and alleviated the stagnation trend of the G1 phase of cell proliferation caused by H2O2. Furthermore, the addition of phloretin simultaneously significantly increased the protein and mRNA expression of heme oxygenase-1 (HO-1) and alleviated the inhibitory phosphorylation of p-nuclear factor erythroid 2-related factor 2 (Nrf2), p-AMP-activated protein kinase (AMPK), and p-liver kinase B1 (LKB1) induced by H2O2. Moreover, the expression of nuclear Nrf2 was higher with phloretin treatment than without phloretin treatment. Overall, phloretin alleviated the proliferation inhibition and apoptosis induced by H2O2 and exerted antioxidant effects via the LKB1/AMPK/Nrf2/HO-1 pathway in C2C12 cells. These results provide insight for the application of phloretin to alleviate oxidative damage to muscle.
Highlights
Skeletal myopathies, which are common in children and adolescents, are characterized by the inability of the skeletal muscle to tolerate fatigue
The morphology of C2C12 cells treated with three concentrations of phloretin, 10, 20, and 40 μmol/L, and co-treated with 500, 750, and 1,000 μmol/L of H2O2 were observed
When the concentration of hydrogen peroxide was 1000 μmol/L, no concentration of phloretin could restore the morphology of the cells to normal (Supplementary Figure S1B); the H2O2 concentrations of 500 and 750 μmol/L were selected for further experiments
Summary
Skeletal myopathies, which are common in children and adolescents, are characterized by the inability of the skeletal muscle to tolerate fatigue. Such muscle damage is caused by abnormal energy supply, mainly via abnormal mitochondrial metabolism in muscle cells (Tarnopolsky, 2016). Angiotensin II, the active component of the renin-angiotensin-aldosterone system, increases mitochondrial ROS production in skeletal muscle (Semprun-Prieto et al, 2011; Sukhanov et al, 2011). Oxidative stress in skeletal muscle induces proteolysis and leads to atrophy (Leitner et al, 2017). The application of drugs and bioactive compounds to relieve oxidative stress caused by ROS is a new direction for the treatment of muscle diseases (Moulin and Ferreiro, 2017)
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