Ricerc@Sapienza

Cancer-associated cachexia is defined by loss of skeletal muscle mass with or without body fat loss. The skeletal muscle regenerative processes appear to be dysregulated in cancer cachexia, with increased muscle progenitor cell proliferation, resulting from systemic inflammation, coupled to hampered myogenic potential, as shown in both animal models and patients. Pax7 and myogenic factor 5 (Myf5) are transcription factors expressed by proliferating satellite cells. Increased expression of these genes indicates higher satellite cell content. We aimed at evaluating skeletal muscle Pax7 and Myf5 mRNA expression and its correlation with markers of systemic inflammation in patients with cancer-associated cachexia. Methods: Patients with gastric, colon and rectal cancer were recruited after signature of the informed consent form. Blood and anthropometric parameters were obtained before surgery for tumor resection, during which rectus abdominis muscle biopsies were collected. Patients with cancer cachexia were allocated in the Cachectic Cancer group (CC, n=16) and compared to patients of the Weight-Stable Cancer group (WSC, n=10). Serum C-reactive protein (CRP), interleukin (IL) -6, -8, tumor necrosis factor (TNF) α, and albumin concentration was measured using commercial kits. Hemoglobin concentration was collected from the patients’ medical records. Muscle mRNA was extracted and real time qPCR was performed, using specific primers for Pax7, Myf5 and GAPDH (housekeeping gene), and results were calculated by the comparative 2-ΔΔCT method. Student’s T-test or Mann-Whitney test were used to compare groups. Spearman correlation analysis was employed to evaluate associations between gene expression and other parameters. Results: Pax7 and Myf5 skeletal muscle gene expression was higher (p=0.02 and p=0.0009, respectively) in CC, who also presented weight loss (p<0.0001), higher serum CPR (p=0.0009), IL-6 (p=0.0064), IL8 (p=0.0365), TNFα (p=0.0183) and lower hemoglobin (p=0.0063), as well as higher CRP/albumin ratio, as compared to WSC. In CC, Pax7 gene expression was associated with weight loss (rs=0.58, p=0.02), increased CRP/albumin ratio (rs=0.67, p=0.0057) and serum IL-6 (rs=0.65, p=0.0259); Myf5 gene expression was correlated with serum IL-6 (r=0.67, p=0.0203). No correlations among the same parameters were observed for WSC. Conclusion: Muscle regeneration is dysregulated in the skeletal muscle of cachectic cancer patients and this is strongly associated with circulating inflammatory factors, which are increased in the weigh-losing patients. Our findings highlight the importance to control systemic inflammation in cachexia.