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.
Cancer cachexia is a multifactorial syndrome associated with poor prognosis and impaired quality of life in cancer patients. However, survival prediction in cancer cachexia remains difficult due to the lack of reliable biomarkers.
This retrospective cohort study analysed data from 1,367 patients with cancer cachexia diagnosed according to the 2011 Fearon consensus, using the multicentre INSCOC database. The cohort was divided into a training set (n = 959), an internal validation set (n = 408), and an independent external validation cohort (n = 284). The mean age of the entire cohort was 58.7 ± 10.9 years, and 39.4% were female. LASSO regression identified creatinine (Cr) as a key predictor. The CCAR (Cr + CAR) index was then constructed using Cr and CAR within a random forest model. Prognostic performance was assessed by Harrell's concordance index (C-index), time-dependent AUC, Kaplan–Meier analysis and multivariate Cox regression, with overall survival (OS) as the primary endpoint.
The CCAR index consistently outperformed conventional inflammation- and nutrition-related markers across all three cohorts. The C-index values for CCAR were 0.777 in the training cohort, 0.789 in the internal validation cohort, and 0.765 in the external validation cohort, compared with 0.627–0.660 for CAR ALONE. Patients in the high-CCAR group had significantly worse OS than those in the low-CCAR group (log-rank p < 0.0001 for all cohorts). Multivariate Cox regression confirmed that CCAR was an independent prognostic factor for OS (HR 3.31, 95% CI 2.94–3.72 in the training set; HR 3.51, 95% CI 2.93–4.22 in the validation set; HR 3.21, 95% CI 2.55–4.03 in the external cohort; all p < 0.001). A web-based calculator (https://heyangzhang.pythonanywhere.com) was developed for real-time CCAR computation and survival predictions.
The CCAR index provides a robust, easily accessible tool for predicting survival outcomes in cancer cachexia patients. The web-based CCAR calculator demonstrates significant clinical applicability and improves patient risk stratification, offering potential for guiding early interventions and personalized treatment strategies in clinical settings.
Lean body mass (LBM) is independently associated with the function and structure of the cardiovascular (CV) system in women and genetically predisposed men with low LBM. Yet, the relationship between LBM and the CV system remains uncertain in the general population comprising a wide spectrum of LBM.
A total of 325 healthy women (n = 162) and men (n = 163) throughout the adult lifespan (18–78 years) matched by age (age = 43 ± 18 vs. 44 ± 18 years) and physical activity were included. Body composition, including LBM, fat and bone mass, was assessed in total and per body region (legs, arms and trunk) by dual-energy x-ray absorptiometry. Left ventricular (LV) mass and structure as well as peripheral and central haemodynamics were determined via echocardiography and continuous blood pressure measurements.
Women presented with lower total LBM (p < 0.001) and higher body fat (p < 0.001) than men. Total LBM did not associate with systolic blood pressure (SBP) in women (p = 256) but did positively associate with SBP in men (r = 0.31, p < 0.001). Total LBM did not associate with LV concentric hypertrophy (LVRWTd) in women (p = 448) but did positively associate with LVRWTd in men (r = 0.24, p = 0.003). Similar sex-specific associations were observed for regional LBM, except for arm LBM, which associated with all study variables in women. Adjustment by body fat or body fat percentage did not modify the results.
Total LBM independently associates with a hypertensive CV phenotype in men, whereas regional LBM, specifically in the arms, is linked with the same detrimental phenotype in women.
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