Long-term effects of the chronic administration of doxorubicin on aged skeletal muscle: An exploratory study in mice

• Published in: Biochemical and biophysical research communications Vol. 733; p. 150650
• Main Authors: Moreira-Pais, Alexandra, Ferreira, Rita, Baltazar, Telmo, Neuparth, Maria João, Vitorino, Rui, Reis-Mendes, Ana, Costa, Vera Marisa, Oliveira, Paula A., Duarte, José A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.11.2024
• Subjects: Aging; caspase-3; Chemotherapy; doxorubicin; drug therapy; energy metabolism; inflammation; males; muscle development; Muscle wasting; muscles; muscular atrophy; myotoxicity; Oxidative stress; quality of life; reactive oxygen species; Sarcopenia; skeletal muscle; Aging; Oxidative stress; Sarcopenia; Chemotherapy; Muscle wasting
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2024.150650

The widely used chemotherapeutic drug doxorubicin (DOX) has been associated with adverse effects on the skeletal muscle, which can persist for years after the end of the treatment. These adverse effects may be exacerbated in older patients, whose skeletal muscle might already be impaired by aging. Nonetheless, the mediators responsible for DOX-induced myotoxicity are still largely unidentified, particularly the ones involved in the long-term effects that negatively affect the quality of life of the patients. Therefore, this study aimed to investigate the long-term effects of the chronic administration of DOX on the soleus muscle of aged mice. For that and to mimic the clinical regimen, a dose of 1.5 mg kg−1 of DOX was administered two times per week for three consecutive weeks in a cumulative dose of 9 mg kg−1 to 19-month-old male mice, which were sacrificed two months after the last administration. Body wasting and the atrophy of the soleus muscle, as measured by a decrease in the cross-sectional area of the soleus muscle fibers, were identified as long-term effects of DOX administration. The atrophy observed was correlated with increased reactive oxygen species production and caspase-3 activity. An impaired skeletal muscle regeneration was also suggested due to the correlation between satellite cells activation and the soleus muscle fibers atrophy. Systemic inflammation, skeletal muscle energy metabolism and neuromuscular junction-related markers do not appear to be involved in the long-term DOX-induced skeletal muscle atrophy. The data provided by this study shed light on the mediators involved in the overlooked long-term DOX-induced myotoxicity, paving the way to the improvement of the quality of life and survival rates of older cancer patients. [Display omitted] •Body wasting and skeletal muscle atrophy are long-term effects of DOX at older ages.•DOX-induced long-term histopathological alterations in aged soleus muscle.•DOX-induced soleus atrophy correlated with high ROS levels and caspase-3 activity.•DOX-induced soleus atrophy might be linked to an impaired muscle regeneration.