Exercise Protects Skeletal Muscle during Chronic Doxorubicin Administration

Area of Science:

• Exercise Physiology
• Molecular Biology
• Cancer Therapeutics

Background:

• Doxorubicin (DOX) is a potent chemotherapy agent with known cardiotoxic and myotoxic side effects.
• Skeletal muscle atrophy and dysfunction are common adverse effects of DOX treatment, impacting patient recovery and quality of life.
• The molecular mechanisms underlying DOX-induced muscle damage, including REDD1 upregulation and mammalian target of rapamycin (mTOR) signaling inhibition, are not fully understood.

Purpose of the Study:

• To investigate the efficacy of exercise training, initiated before and continued during biweekly doxorubicin (DOX) administration, in mitigating DOX-induced skeletal muscle toxicity.
• To test the hypothesis that DOX treatment increases REDD1, impairs mTOR signaling, and reduces muscle fiber size, and that exercise training can attenuate these detrimental effects.

Main Methods:

• Ovariectomized female Sprague-Dawley rats underwent four treatment conditions: exercise + DOX (Ex-Dox), exercise + vehicle (Ex-Veh), sedentary + DOX (Sed-Dox), and sedentary + vehicle (Sed-Veh).
• DOX (12 mg·kg cumulative dose) or vehicle was administered intraperitoneally biweekly for three injections.
• Interval exercise (85%-90% V˙O2peak) was performed 5 days/week, starting 1 week before the first DOX injection and continuing throughout the study. Soleus muscles were analyzed via immunoblot and immunohistochemistry.

Main Results:

• Sedentary DOX-treated rats (Sed-Dox) exhibited increased REDD1 mRNA and protein, alongside reduced mTOR and 4E-BP1 phosphorylation and decreased MHC I and MHC IIa fiber size compared to sedentary controls (Sed-Veh).
• Exercise training in DOX-treated rats (Ex-Dox) prevented the DOX-induced increases in REDD1 and maintained mTOR/4E-BP1 signaling and MHC I fiber size compared to exercise-only controls (Ex-Veh).
• Autophagy markers (LC3BI, LC3BII/I ratio) were altered in Sed-Dox but not in Ex-Dox rats, suggesting exercise modulates DOX-related cellular stress responses.

Conclusions:

• Doxorubicin treatment may induce skeletal muscle toxicity by increasing REDD1 and inhibiting mTORC1 signaling, leading to reduced muscle fiber size.
• Exercise training initiated before and continued during DOX administration effectively attenuates these molecular and structural changes in skeletal muscle.
• Exercise represents a promising therapeutic strategy to preserve skeletal muscle mass and function in patients undergoing chronic doxorubicin chemotherapy.