Mitochondrial Respiratory Capacity and Coupling Control of Skeletal Muscle in Colon-26 Tumor-Induced Cachexia

Abstract

Cancer cachexia is a life-threatening, paraneoplastic syndrome featuring unintended weight loss and skeletal muscle atrophy. Mitochondria, the major providers of cellular energy, couple oxygen consumption to ATP synthesis (i.e. oxidative phosphorylation, OXPHOS). Impaired mitochondrial bioenergetics (e.g. respiration) is associated with the pathophysiology of multiple diseases. The control of mitochondrial respiration in skeletal muscle during the induction and progression of cancer cachexia is not well understood. PURPOSE: To investigate mitochondrial respiratory capacity and coupling control of skeletal muscle in the colon-26 model of cancer cachexia. METHODS: Balb/c males (10 wks) were assigned to control or colon-26 (C26). C26 mice were injected with 1x106 tumor cells, and tissue collected on days 7, 14, and 21 post-injection. In this model, mice develop palpable tumors at day 7, and cachexia by day 21. Controls were injected with PBS and tissue collected on day 0. Respiration was measured in permeabilized fibers from the medial gastrocnemius via high-resolution respirometry. A substrate-uncoupler-inhibitor titration protocol was used to evaluate Complex I OXPHOS (CIP), Complex I+II OXPHOS (CI+IIP), and electron transfer system capacity (ETS). Efficiency of the OXPHOS system was determined from the ratio CI+IIP/ETS (P/E). RESULTS: CIP was significantly lower (p<0.05) at day 21 (4.8±1.6 pmol/s/mg) in comparison to day 0 (53.4±7.0), day 7 (57.4±6.5), and day 14 (60.0±2.9). CI+IIP was significantly lower (p<0.05) at day 21 (22.3±2.3 pmol/s/mg) in comparison to day 0 (65.5±7.8), day 7 (69.3±8.5), and day 14 (73.8±4.8). Maximal ETS was significantly lower (p<0.05) at day 21 (24.1 pmol/s/mg) in comparison to day 0 (83.7±13.8), day 7 (84.4±12.3), and day 14 (105.1±7.3). P/E was not significantly different across timepoints (p>0.05). CONCLUSION: Phosphorylating respiration with electron input from Complex I and I+II, and maximal electron transfer system capacity (i.e. non-coupled respiration) was significantly reduced at day 21 concomitant with cachexia, but not at earlier timepoints, suggesting that changes in oxidative metabolism occur as a consequence of cachexia rather than having a causative role. Loss of respiratory capacity may compromise muscle function and physical independence.