Jacob L. Brown1, Megan E. Rosa1, David E. Lee1, Richard A. Perry1 Jr., Lemuel A. Brown1, Michael P. Wiggs2, Tyrone A. Washington1, Nicholas P. Greene1. 1University of Arkansas, Fayetteville, 2University of Texas at Tyler.

Cancer is associated with severe weight and muscle loss (cancer-cachexia). Cancer-cachexia is the most common manifestation of the advanced malignant disease, leading to death. Underlying mechanisms of cancer-cachexia are not well understood. Mitochondrial degeneration is associated with cancer-cachexia and may instigate skeletal muscle atrophy through pathways affiliated with reactive oxygen species signaling and energy demand. PURPOSE: Assess mitochondrial quallity and function throughout the progression of cancer-cachexia. METHODS: Lewis Lung Carcinoma cells (LLC) or Phosphate Buffered Saline (PBS, control) were injected into the hind-flank of C57Bl6/J mice at 8 weeks age, and tumor allowed to develop for 1, 2, 3 or 4 weeks. Muscle size was assessed by muscle wet weights and cross sectional area (CSA). Mitochondrial function was assessed in permeabilized adult myofibers for each time point. In order to measure mitochondrial degeneration, the reporter gene pMitotimer were inserted to the Flexor Digitorum Brevis muscle 2 weeks before LLC or PBS injection and imaged in whole-mounted muscle at harvest by fluorescence microscopy. RESULTS: Muscle wet weights were significantly decreased by ~10-20% at 4 weeks post LLC implantation when compared to PBS. Average CSA decreased by ~40% by 4-week post LLC implantation. Mitochondrial function was disrupted by 3-week post LLC implantation indicated by a ~25% decrease in Respiratory Control Ratio. Mitochondria displayed significant signs of degeneration by 2-weeks post LLC implantation when compared to PBS control, portrayed by a 50% increase in pMitotimer Red/Green ratio, indicating general degeneration of the network, and 400% increase in pure red puncta, revealing the presence of completely degenerated mitochondria marked for degradation. CONCLUSION: Mitochondrial degeneration appears to occur prior to the onset of skeletal muscle atrophy in the progression of cancer-cachexia. This study indicates novel potential early stage mechanisms leading to muscle wasting in cancer-cachexia.

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