Age, cancer, and the dual burden of cancer and doxorubicin in skeletal muscle wasting in female rats: which one to blame?

Abstract

Sarcopenia and cancer cachexia are two life-threatening conditions often misdiagnosed. The skeletal muscle is one of the organs most adversely affected by these conditions, culminating in poor quality of life and premature mortality. In addition, it has been suggested that chemotherapeutic agents exacerbate cancer cachexia, as is the case of doxorubicin. Herein, we sought to investigate markers of inflammation and neuromuscular junction (NMJ) remodeling during aging and in response to cancer or cancer with chemotherapy. To address this, we utilized female rats across three age groups - young, adult, and old - to examine age-related changes, with old rats serving as a sarcopenia model. Additionally, a chemically-induced breast cancer (BCa) model was implemented in female adult rats, both without (adult BCa) or with doxorubicin administration (adult BCaDOX), to study cancer cachexia. The atrophy of the gastrocnemius muscle was observed in old, adult BCa and adult BCaDOX rats compared to adult ones. No signs of inflammation or NMJ impairment were observed in adult BCa or adult BCaDOX rats, except for the low levels of the subunit α1 of the acetylcholine receptor in adult BCaDOX rats compared to adult ones. In contrast, old rats presented high serum levels of interleukin 6, brain-derived neurotrophic factor (BDNF) and calcitonin gene-related peptide compared to young rats. In the gastrocnemius muscle, BDNF levels were decreased in old rats compared to adult rats, suggesting impaired skeletal muscle regeneration upon age-induced damage. The BDNF muscle levels were inversely correlated with its levels in circulation in adult and old rats. Hence, this work highlights BDNF as a specific biomarker of age-induced skeletal muscle atrophy, at least, in the differential diagnosis against cancer- or cancer with chemotherapy-induced muscle wasting.