title: Exercise protects against doxorubicin-induced markers of autophagy signaling in skeletal muscle.
abstract: Doxorubicin (DOX) is an effective antitumor agent used in cancer treatment. Unfortunately, DOX is also toxic to skeletal muscle and can result in significant muscle wasting. The cellular mechanism(s) by which DOX induces toxicity in skeletal muscle fibers remains unclear. Nonetheless, DOX-induced toxicity is associated with increased generation of reactive oxygen species, oxidative damage, and activation of the calpain and caspase-3 proteolytic systems within muscle fibers. It is currently unknown if autophagy, a proteolytic system that can be triggered by oxidative stress, is activated in skeletal muscles following DOX treatment. Therefore, we tested the hypothesis that systemic administration of DOX leads to increased expression of autophagy markers in the rat soleus muscle. Our results reveal that DOX administration results in increased muscle mRNA levels and/or protein abundance of several important autophagy proteins, including: Beclin-1, Atg12, Atg7, LC3, LC3II-to-LCI ratio, and cathepsin L. Furthermore, given that endurance exercise increases skeletal muscle antioxidant capacity and protects muscle against DOX-induced oxidative stress, we performed additional experiments to determine whether exercise training before DOX administration would attenuate DOX-induced increases in expression of autophagy genes. Our results clearly show that exercise can protect skeletal muscle from DOX-induced expression of autophagy genes. Collectively, our findings indicate that DOX administration increases the expression of autophagy genes in skeletal muscle, and that exercise can protect skeletal muscle against DOX-induced activation of autophagy.
authors.affiliation: Department of Applied Physiology and Kinesiology, Center for Exercise Science, University of Florida, Gainesville, Florida, USA.
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Smuder
authors.forename: Andreas N
authors.initials: AN
authors.lastname: Kavazis
authors.forename: Kisuk
authors.initials: K
authors.lastname: Min
authors.forename: Scott K
authors.initials: SK
authors.lastname: Powers
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D002154:Calpain / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D010805:Physical Conditioning, Animal / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D011506:Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C018589:lysosomal proteins; D004317:Doxorubicin; D010447:Peptide Hydrolases; D002154:Calpain; D053148:Caspase 3