Sarcopenia vs. Cachexia: Explaining Skeletal Muscle Wasting on Aging, Breast Cancer or Chemotherapy in Preclinical Models

Abstract

The overarching aim of this thesis was to delve into the molecular mechanisms underlying age-, cancer- and/or chemotherapy-induced skeletal muscle remodeling and the mediators that might retain propitious clinical differential value. To better understand the age-induced skeletal muscle remodeling and the role of sex, the proteome of mitochondria-enriched fractions isolated from the gastrocnemius of young and old, female and male rats was analyzed. The results demonstrated an age-induced compromised oxidative phosphorylation, increased fatty acid oxidation and higher proneness of the mitochondrial proteins to oxidative modifications, possibly triggered by diminished levels of 17beta-estradiol in serum and of estrogen receptor alpha in mitochondria. These alterations appear to have contributed to the atrophy and fibrosis noticed in the gastrocnemius of old females. With the purpose of distinguish the molecular foundations underlying the skeletal muscle wasting that characterizes sarcopenia and cancer cachexia, the gastrocnemius of young, adult and old female rats, and of adult female rats with chemically-induced breast cancer was explored. The results revealed that inflammation (increased serum levels of interleukin-6) and decreased muscle levels of brain-derived neurotrophic factor seem to exclusively contribute to the loss of skeletal muscle induced by aging. The long-term molecular alterations of the chronic administration of doxorubicin were investigated in the soleus of old mice. The results evinced the atrophy of the soleus associated with elevated levels of myostatin and an increased carbonylation of muscle proteins. In conclusion, the atrophy of the skeletal muscle induced by aging involves the dysfunction of the mitochondrion (in a sex-specific manner) and of the skeletal muscle regeneration associated, in part, to the presence of systemic inflammation. These mechanisms seem not to participate in cancer-induced skeletal muscle atrophy. The long-term skeletal muscle atrophy prompted by the chronic administration of doxorubicin seems to be ensued from proteolysis and a compromised skeletal muscle regeneration.