Prevention of Doxorubicin-Induced Autophagy Attenuates Oxidative Stress and Skeletal Muscle Dysfunction

Area of Science:

• Biochemistry
• Cellular Biology
• Muscle Physiology

Background:

• Doxorubicin (DOX) chemotherapy is known to induce skeletal muscle atrophy and weakness.
• Reactive oxygen species (ROS) production is implicated in DOX-induced muscle dysfunction.
• Autophagy, a cellular degradation process, is upregulated by DOX in skeletal muscle.

Purpose of the Study:

• To investigate the specific role of accelerated autophagy in doxorubicin-induced skeletal muscle dysfunction.
• To determine if inhibiting autophagy can mitigate DOX-induced skeletal muscle atrophy and weakness.

Main Methods:

• Inhibition of autophagy in the soleus muscle of rats using a dominant-negative mutation of autophagy-related protein 5 (ATG5).
• Administration of doxorubicin (DOX) to assess muscle atrophy, contractile function, and mitochondrial ROS levels.
• Analysis of gene expression related to antioxidant response and mitochondrial biogenesis.

Main Results:

• Targeted inhibition of autophagy prevented acute soleus muscle atrophy and contractile dysfunction following DOX administration.
• Autophagy inhibition reduced mitochondrial ROS production and maintained mitochondrial respiratory capacity.
• Significant upregulation of antioxidant and mitochondrial biogenesis genes (e.g., PPARGC1A, NRF-1, NFE2F2, NQO1, CAT) was observed when autophagy was inhibited.

Conclusions:

• Accelerated autophagy plays a significant role in the development of oxidative stress and skeletal muscle weakness induced by doxorubicin.
• Inhibiting autophagy is a potential therapeutic strategy to counteract doxorubicin-induced muscle toxicity.
• The protective effects of autophagy inhibition are linked to reduced oxidative stress and enhanced antioxidant capacity.