## 1 Introduction  
Cancer is a significant public health concern worldwide because its cases continue to arise. Currently, cancer remains an incurable disease, but an opportune chemotherapeutic strategy suppresses cancer growth and thus extends a lifespan. Doxorubicin (DOX) is the most widely administered chemotherapeutic agent; however, several side effects, such as severe nausea, vomiting, and alopecia are inevitable. Moreover, DOX's toxicity to normal cells has been a primary clinical concern. Specifically, DOX-induced muscle loss and mortality have remained a critical topic among chemotherapy-mediated side effects [1; 2; 3; 4; 5]. While pharmacological and nutritional interventions to mitigate DOX-induced myotoxicity have shown inconsistent results, preclinical studies have shown that endurance exercise (EXE) confers protection against myotoxicity in skeletal muscle. For instance, administration of acute endurance exercise (EXE) before an acute DOX treatment protects against DOX-induced myotoxicity [6; 7]. However, given that most clinical chemotherapy paradigms consisting of multiple cycles of DOX treatment are administered, it is imperative to investigate whether prolonged EXE as an adjuvant intervention during chronic DOX treatment can appease myotoxicity to simulate a clinical setting of DOX treatment. Moreover, potential protective molecular mechanisms mediated by chronic EXE against DOX-induced myotoxicity remain unknown. The exact mechanism of DOX-induced myotoxicity in skeletal muscle is not fully understood yet. However, the fact that DOX's random interposition to deoxyribonucleic acid (DNA) in parallel with topoisomerase II\(\beta\) (TOP2B) results in damaging DNA in cardiomyocytes sheds light on how DOX causes myotoxicity [8; 9]. More specifically, a recent study has shown that DOX-induced downregulation of TOP2B protein expression promotes cell death via increasing oxidative stress in cardiomyocytes [10]; in contrast, another study has reported that deletion of TOP2B prevents the heart against DOX-induced cardiotoxicity [11]. These conflicting reports suggest that more studies are necessary to verify the underlying role of TOP2B in myotoxicity. More importantly, whether DOX-induced TOP2B modulation is linked to myotoxicity in skeletal muscle remains unknown. Besides, no literature is available if EXE-mediated modulation of TOP2B is associated with myocyte protection against DOX-induced myotoxicity. Satellite cells are skeletal muscle-specific stem cells crucially contributing to repairing muscle damage and injury. Activation of myogenic regulatory factors (MRFs), such as paired box 7 (PAX7), myogenic differentiation 1 (MYOD 1), and myogenin (MYOG) are necessary for satellite cells to be proliferated and differentiated into mature myotubes [12; 13]. Recent evidence has shown that DOX-induced dysregulation of MRFs is associated with myocyte regenerative dysfunction, but acute EXE-induced MRF restoration improves regenerative capacity against DOX [14], suggesting that EXE-induced satellite cell amelioration may be a potential protective mechanism against DOX. However, whether chronic EXE elicits the same protective mechanisms against DOX-induced myotoxicity remains unknown. Accelerated protein degradation due to DOX administration has been suggested as a potent element in DOX-induced muscle atrophy. In this regard, the ubiquitin-proteasome system (UPS) plays a crucial role in proteolysis. The UPS consists of E1 ubiquitin-activating enzyme, E2 ubiquitin conjugation, and E3 ubiquitin ligase, among which the E3 ubiquitin ligase facilitates ubiquitination to a target protein for degradation by the 26S proteosomes. Therefore, modulations of E3 ligase expression have been implicated in various models of muscle atrophy. Specifically, two muscle-specific E3 ligases, such as muscle atrophy F-box (MAFbx)/atrogin-1 and muscle ring-finger-1 (MuRF-1) in the skeletal muscle have been identified as potent inducers of muscle atrophy [15].