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

## TL;DR

Early-stage colon cancer reduces muscle energy metabolism by impairingly mitochondrial function, potentially leading to muscle loss before symptoms appear.

## Contribution

Identifies early mitochondrial complex I suppression in primary colon cancer as a novel mechanism for muscle dysfunction.

## Key findings

- Primary-stage colon cancer reduces mitochondrial complex I activity in skeletal muscle compared to controls.
- Early-stage cancer shows compensatory upregulation of OXPHOS-related genes, unlike advanced stages.
- Mitochondrial impairments occur before physical decline or systemic inflammation signs.

## Abstract

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.

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.

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).

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.