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Subclinical Myopathy and Colorectal Cancer: Identification and Role of New Muscle Damage and Regeneration Biomarkers
Mario Gruppo*1, Renato Salvador1, Mario Bernardo3, Gianpietro Zanchettin1, Cosimo Sperti1, Michele Valmasoni1, Gianfranco Da Dalt1, Stefano Merigliano1, Ugo Carraro2, Sandra Zampieri2
1Department of Surgery, Oncology and Gastroenterology, University Hospital of Padua, Padova, Italy; 2Department of Biomedical Sciences, University Hospital of Padua, Padova, Italy; 3University of Tor Vergata, Rome, Italy
Background
Skeletal muscle is the major reservoir of body proteins and it can be particularly affected in conditions associated to altered protein turnover and metabolism such as cancer. Although severe wasting is seen primarily in patients with advanced malignancy or cachexia, some of them present degree of wasting at clinical presentation.
Materials and Methods
We performed morphometric studies and immunohistochemical analyses on intraoperative rectus abdominis muscle biopsies from 54 consecutive weight stable colorectal patients and 37 weight-stable patients operated for non-inflammatory benign diseases with no signs of muscle weakness or myopathies.
We also performed analyses on serum samples collected prior to surgery. We tested markers of inflammation (C Reactive Protein, CRP), muscle enzymes, (Creatin Kinase, CK), soluble isoform of NCAM), and markers of protein turnover. We also performed follow-up visits of all patients and controls to collect clinical outcome data.
Results
In cancer patients, we observed a subclinical myopathy characterized by an abnormal distribution of myonuclei relocated from the periphery inside the myofiber, and by the presence of regenerating muscle fibers. The percentage of myofibers with abnormally located myonuclei was significantly higher in patients (median= 9%, IQR= 3.7-18.8) compared to controls (median= 2.7%, IQR= 1.7-3.2) (p=0.0002). Analyses on serum samples showed that in the absence of systemic inflammation, in the prevalence of cancer patients the levels of albumin and prealbumin were below the normal range (albumin 35-53 g/L; prealbumin 200-400 mg/L), and the mean value was significantly lower compared to that detected in controls (albumin: 34.82 ± 5.8 g/L vs 45.2 ± 5.3, p< 0.01; prealbumin: 174.38±57.86 mg/L vs 264.00±69.73, p<0.001)(Fig 1). Follow-up was 38 ± 12 months. Deceases in patients' group were 16.6% (9/54) and cancer relapse occurred in 29.6% (16/54) patients. We found an inverse correlation between the number of abnormally nucleated myofibers and the presence of lymph node metastasis (N+) (ñ)=-0.64 (p=0.002). Cancer relapse was correlated with low serum levels of prealbumin (156.59 ± 44.22 mg/L in cancer relapse vs 190.62 ± 57.23 mg/L in patients without relapse; p = 0.08)(Fig 2).
Conclusions
Colorectal cancer patients have a subclinical myopathy characterized by myofibers with internally located myonuclei and signs of regeneration. In the absence of inflammation, cancer patients show low levels of prealbumin and albumin as markers of altered protein turnover. Up to now our data indicate the myopathy and altered protein turnover appear to be associated to an early stage of colorectal cancer; in particular, relocation and redistribution of myofiber nuclei seem to be associated with better disease prognosis, while altered protein turnover seems to be predictive for colorectal cancer relapse.
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