Background
Skeletal muscle is the major reservoir of body proteins and it can be affected in conditions associated to altered protein turnover and metabolism such as cancer. Although severe wasting is seen primarily in patients with advanced malignancy, some of them present degree of wasting at the onset of disease. Autophagy has been recently described to play a relevant role in muscle wasting.
Materials and Methods
We performed morphometric studies and immunohistochemical analyses on intraoperative rectus abdominis muscle biopsies from 50 consecutive weight stable colorectal patients and 25 weight-stable patients operated for non-inflammatory benign diseases with no clinical signs of myopathies. Biochemical and molecular analyses have been performed in order to evaluate protein profile, the presence of autophagy induction and their correlation with clinical outcome.
Results
In cancer patients, we observed a subclinical myopathy characterized by an abnormal distribution of myonuclei relocated from the periphery inside the myofiber. The percentage of myofibers with abnormally located myonuclei was significantly higher in patients compared to controls. 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 and the mean value was significantly lower compared to that detected in controls. Molecular analyses showed an accumulation of p62, a typical marker of autophagy induction, significantly higher in cancer patients compared to controls. We found an inverse correlation between the number of abnormally nucleated myofibers and the presence of lymph node metastasis. Cancer relapse was correlated with low serum levels of prealbumin and high levels of p62 in myofibers of cancer patients.
Conclusions
Colorectal cancer patients have a subclinical myopathy characterized by myofibers with internally located myonuclei. In the absence of inflammation, cancer patients show low levels of prealbumin and albumin as markers of altered protein turnover and persistent high levels of p62 in myofibers as expression of autophagy induction with an impairment in physiological autophagic flux. Up to now our data indicate that skeletal muscle fibers show nuclear abnormalities that seems to be associated to a better prognosis, while the presence of an altered protein turnover at an early stage of disease, with an impairment in the physiological autophagic flux, that could be predictive of cancer relapse and onset of cancer cachexia
