Primary‐Stage Colon Cancer Impairs Muscle Energy Metabolism by Suppressing Mitochondrial Complex I Activity

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BACKGROUND: Colon cancer (CC), the third most common cancer worldwide, is accompanied by cachexia in 30% of patients. Its associated muscle loss directly impairs therapeutic response and survival. Early intervention is crucial, yet the underlying mechanisms of early-stage muscle dysfunction remain unclear. This study investigates mitochondrial function in skeletal muscle across different CC stages to identify early metabolic alterations. METHODS: The present study investigated mitochondrial function in rectus abdominus muscle biopsies from 30 patients with primary CC (83% male, mean age 67 ± 8 years), 10 patients with colorectal cancer with liver metastases (50% male, mean age 69 ± 6 years), and 17 age-matched controls (65% male, mean age 66 ± 7 years). Mitochondrial oxygen consumption was assessed using high-resolution respirometry, and transcriptional profiles were analysed via RNA sequencing. RESULTS: Patients with primary CC exhibited reduced complex I activity compared to controls (9.02 vs. 12.47 pmol/s/mg, p < 0.001), accompanied by transcriptional upregulation of oxidative phosphorylation (OXPHOS)-related genes. In contrast, patients with liver metastases showed more severe mitochondrial dysfunction, with reductions in both complex I (7.38 vs. 9.65 pmol/s/mg, p < 0.01) and complex II (8.36 vs. 19.73 pmol/s/mg, p < 0.05), but without the compensatory transcriptional upregulation seen in primary CC. These mitochondrial impairments occurred before detectable declines in physical function or systemic inflammation (C-reactive protein, albumin). CONCLUSIONS: Our findings reveal stage-specific mitochondrial dysfunction in CC, with early complex I impairment and a transient transcriptional adaptation in primary CC. These alterations precede clinical cachexia, suggesting mitochondrial dysfunction as a potential early biomarker for cancer-induced muscle loss and a target for early intervention.

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