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

Area of Science:

• Mitochondrial biology
• Oncology
• Muscle physiology

Background:

• Colon cancer (CC) is a leading cause of cancer mortality worldwide.
• Cachexia, characterized by muscle wasting, affects 30% of CC patients, impairing treatment outcomes and survival.
• Mechanisms of early muscle dysfunction in CC remain poorly understood, necessitating investigation into metabolic alterations.

Purpose of the Study:

• To investigate mitochondrial function in skeletal muscle across different stages of colon cancer.
• To identify early metabolic alterations associated with muscle dysfunction in colon cancer.
• To explore the relationship between mitochondrial changes and the onset of cachexia.

Main Methods:

• Analysis of rectus abdominis muscle biopsies from patients with primary CC, metastatic CC, and age-matched controls.
• Assessment of mitochondrial oxygen consumption using high-resolution respirometry.
• Evaluation of gene expression profiles related to oxidative phosphorylation via RNA sequencing.

Main Results:

• Primary CC patients showed reduced Complex I activity with compensatory upregulation of oxidative phosphorylation genes.
• Patients with liver metastases exhibited more severe mitochondrial dysfunction (Complex I and II reductions) without compensatory gene upregulation.
• Mitochondrial impairments were detected prior to significant declines in physical function or systemic inflammation markers.

Conclusions:

• Colon cancer is associated with stage-specific mitochondrial dysfunction in skeletal muscle.
• Early Complex I impairment and transcriptional adaptation occur in primary CC, preceding clinical cachexia.
• Mitochondrial dysfunction may serve as an early biomarker for cancer-induced muscle loss and a therapeutic target.