Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness

Abstract

Cancer cachexia is a syndrome characterized by profound cardiac and diaphragm muscle wasting, which increase the risk of morbidity in cancer patients due to failure of the cardiorespiratory system. In this regard, muscle relies greatly on mitochondria to meet energy requirements for contraction and mitochondrial dysfunction can result in muscle weakness and fatigue. In addition, mitochondria are a major source of reactive oxygen species (ROS) production, which can stimulate increased rates of muscle protein degradation. Therefore, it has been suggested that mitochondrial dysfunction may be an underlying factor that contributes to the pathology of cancer cachexia. To determine if pharmacologically targeting mitochondrial dysfunction via treatment with the mitochondria-targeting peptide SS-31 would prevent cardiorespiratory muscle dysfunction, colon 26 (C26) adenocarcinoma tumor-bearing mice were administered either saline or SS-31 daily (3 mg/kg/day) following inoculation. C26 mice treated with saline demonstrated greater ROS production and mitochondrial uncoupling compared to C26 mice receiving SS-31 in both the heart and diaphragm muscle. In addition, saline-treated C26 mice exhibited a decline in left ventricular function which was significantly rescued in C26 mice treated with SS-31. In the diaphragm, muscle fiber cross-sectional area of C26 mice treated with saline was significantly reduced and force production was impaired compared to C26, SS-31-treated animals. Finally, ventilatory deficits were also attenuated in C26 mice treated with SS-31, compared to saline treatment. These data demonstrate that C26 tumors promote severe cardiac and respiratory myopathy, and that prevention of mitochondrial dysfunction is sufficient to preclude cancer cachexia-induced cardiorespiratory dysfunction. Author contributions AJS, HHS and ARJ designed the study. AJS, BMR, MPW, OK, JY, DDC and DDF performed the experiments and analyzed the data. HHS provided the SS-31. AJS and ARJ wrote the manuscript. All authors reviewed and approved the final version of the manuscript.

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

“…Findings from both preclinical and clinical studies confirm that the hallmarks of cancer cachexia are decreased myofiber cross-sectional area, disrupted muscle ultrastructure, and increased fibrosis [ 35 , 135 , 136 , 137 , 138 ]. Both depressed protein synthesis and accelerated proteolysis have been observed with muscle wasting due to cancer cachexia [ 139 , 140 , 141 , 142 ].…”

“…Direct evidence also indicates that denervation-induced skeletal muscle wasting is also accompanied by increased mitochondrial ROS production [ 33 ]. Further, increases in mitochondrial ROS emissions are observed with age-related loss of skeletal muscle mass (i.e., sarcopenia), cancer, and treatment with doxorubicin (a chemotherapeutic drug) [ 30 , 34 , 35 ]. Together, these studies confirm that increased mitochondrial ROS production accompanies the muscle wasting associated with these conditions.…”

“…Recently, Brown et al provided evidence that mitochondrial dysfunction precedes the development of cachexia in rodent models of lung and colorectal cancer [ 138 ]. Further, pharmacological targeting of mitochondria with the small peptide SS-31 has been shown to attenuate muscle wasting in a rodent model of colon cancer [ 35 ]. Collectively, these studies implicate mitochondrial dysfunction as a key contributor to muscle wasting.…”

“…As discussed previously, chronic elevation in mitochondrial ROS emissions can elicit muscle wasting. Evidence from preclinical models show that mitochondrial ROS emissions increase with cancer cachexia and are accompanied by increased markers of oxidative stress [ 35 , 138 , 139 , 150 , 151 ]. In contrast to these findings, some studies have reported decreased markers of muscle oxidative stress, and that exacerbated oxidative stress does not accentuate cancer cachexia [ 146 , 152 ].…”

Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia

“…Wasting of voluntary skeletal muscles is considered the main hallmark of cancer cachexia; however, cardiac and respiratory muscle dysfunction have been shown to occur in parallel [ 35 , 36 ], potentially contributing to systemic energy wasting. A recently published paper shows that SS-31 is able to counteract cardiorespiratory muscle weakness, alleviating cardiac and respiratory myopathy in mice bearing C26 tumors [ 37 ]. The study has several differences as compared to the current one, including animal sex, that may impact on cachexia susceptibility and mitochondria profiles [ 38 ], the use of a distinct C26 clone, inducing cachexia slowly, and finally mice were not exposed to chemotherapy.…”