MitoTEMPOL, a mitochondrial targeted antioxidant, prevents sepsis-induced diaphragm dysfunction

Abstract

Clinical studies indicate that sepsis-induced diaphragm dysfunction is a major contributor to respiratory failure in mechanically ventilated patients. Currently there is no drug to treat this form of diaphragm weakness. Sepsis-induced muscle dysfunction is thought to be triggered by excessive mitochondrial free radical generation; we therefore hypothesized that therapies that target mitochondrial free radical production may prevent sepsis-induced diaphragm weakness. The present study determined whether MitoTEMPOL, a mitochondrially targeted free radical scavenger, could reduce sepsis-induced diaphragm dysfunction. Using an animal model of sepsis, we compared four groups of mice: 1) sham-operated controls, 2) animals with sepsis induced by cecal ligation puncture (CLP), 3) sham controls given MitoTEMPOL (10 mg·kg−1·day−1 ip), and 4) CLP animals given MitoTEMPOL. At 48 h after surgery, we measured diaphragm force generation, mitochondrial function, proteolytic enzyme activities, and myosin heavy chain (MHC) content. We also examined the effects of delayed administration of MitoTEMPOL (by 6 h) on CLP-induced diaphragm weakness. The effects of MitoTEMPOL on cytokine-mediated alterations on muscle cell superoxide generation and cell size in vitro were also assessed. Sepsis markedly reduced diaphragm force generation. Both immediate and delayed MitoTEMPOL administration prevented sepsis-induced diaphragm weakness. MitoTEMPOL reversed sepsis-mediated reductions in mitochondrial function, activation of proteolytic pathways, and decreases in MHC content. Cytokines increased muscle cell superoxide generation and decreased cell size, effects that were ablated by MitoTEMPOL. MitoTEMPOL and other compounds that target mitochondrial free radical generation may be useful therapies for sepsis-induced diaphragm weakness.

Mitochondrial Dysfunction Is a Common Denominator Linking Skeletal Muscle Wasting Due to Disease, Aging, and Prolonged Inactivity

“…Preclinical and human studies have consistently shown that mitochondrial complex gene expression, protein abundance, and activity are decreased with sepsis [ 162 , 163 , 165 , 167 , 171 , 172 ]. This decrease in oxidative phosphorylation (OXPHOS) machinery also corresponds to decreased ATP content in muscle [ 162 , 165 , 171 , 173 , 174 , 175 ]. In addition to the decrease in OXPHOS machinery, decreased energy availability may also be exacerbated by a decreased ability to distribute energy from the mitochondria throughout the myofiber.…”

“…Indeed, increased mitochondrial ROS emissions may contribute to sepsis-induced muscle wasting. Several reports have shown that muscle mitochondrial ROS emissions are increased with sepsis [ 172 , 175 , 181 , 182 ]. The importance of sepsis-induced mitochondrial ROS is demonstrated by time-course studies showing that increases in mitochondrial superoxide production correlate with the decreases in muscle force production during sepsis [ 172 ].…”

“…The importance of sepsis-induced mitochondrial ROS is demonstrated by time-course studies showing that increases in mitochondrial superoxide production correlate with the decreases in muscle force production during sepsis [ 172 ]. Moreover, mitochondrial targeted antioxidants prevent sepsis-induced contractile dysfunction in diaphragm muscle [ 175 , 182 ]. These studies provide strong evidence for the importance of mitochondrial dysfunction with sepsis; however, these studies did not measure muscle cross-sectional area, and direct evidence on mitochondrial dysfunction in sepsis-induced muscle wasting is limited.…”

Protective Effect of Mitochondria-Targeted Antioxidants against Inflammatory Response to Lipopolysaccharide Challenge: A Review

“…Numerous animal models of sepsis (LPS or CLP) have demonstrated common abnormalities: increased level of ROS, decreased antioxidant capacity, and mitochondrial oxidative damage [ 14 , 15 , 74 ]. LPS-triggered generation of mitochondrial superoxide measured usually with the fluorogenic dye MitoSOX was demonstrated in different cell types, such as microglia [ 75 , 76 ], muscle myoblasts [ 23 ], gingival fibroblasts [ 17 ], human pulmonary bronchial epithelial cells [ 77 ], macrophages [ 78 ], and others. In addition, the decline in antioxidative enzymes and glutathione content caused by LPS contributes to the impairment of endogenous antioxidant defense and the subsequent increase in mtROS generation [ 79 , 80 , 81 , 82 , 83 ].…”

“…Impairment of mitochondria plays a critical role in inducing cell apoptosis and tissue damage in different inflammatory states. Evidence indicates that endotoxemia is accompanied by a significant elevation in mitochondrial ROS (mtROS) generation, impairment of the electron transfer chain (ETC) and oxygen consumption, reduction in the mitochondrial membrane potential (MMP), deficiency in ATP production, decline in the endogenous antioxidant capacity, and accumulation of lipid peroxidation products [ 19 , 20 , 21 , 22 , 23 ]. mtROS are also able to stimulate NADPH oxidase activity, enhancing the cytosolic ROS level [ 24 ].…”