Effects of endurance exercise and doxorubicin on skeletal muscle myogenic regulatory factor expression

Abstract

Background: The skeletal muscle toxicity that accompanies the chemotherapy drug doxorubicin (DOX) may lead to cancer patient weakness and fatigue. This myotoxicity involves myogenic regulatory factor (MRF) disruption which alters muscle integrity and regeneration. Endurance exercise enhances MRF expression and thereby may mitigate DOX-induced MRF disruptions. This study examined the effects of endurance training and DOX treatment on myogenic regulatory factor (MRF) expression.

Methods: Male rats were exercise trained (EXER) or remained sedentary (SED) for two weeks. EXER and SED then received either DOX (15 mg/kg) or saline (SAL). Soleus, extensor digitorum longus (EDL), and diaphragm were excised 24 hours post injection, and MRF expression was analyzed.

Results: Significant Myf5 drug and activity effects were observed in the soleus with EXER+DOX expressing higher Myf5 than SED+DOX. A significant drug effect was detected in soleus MyoD, and a significant activity effect was detected in soleus Mrf4. No main effects or interactions were observed in the EDL, but in the diaphragm, a significant activity effect was observed for Myf5 with EXER+DOX expressing higher levels than SED+DOX.

Conclusion: Doxorubicin treatment increased soleus MRFs and exercise boosted MRF response in soleus and diaphragm suggesting that exercise may enhance regenerative signaling with DOX treatment.

Level of evidence: I b, individual randomized controlled trial.

Keywords: anthracycline; diaphragm; fast muscle; slow muscle.

Figure 1

Myf5 expression in the soleus (A), extensor digitorum longus (B), and diaphragm (C). Data are mean ± SEM. SED, sedentary; EXER, treadmill exercise trained; SAL, saline injection; DOX; doxorubicin injection. † Main exercise effect (p<0.05) ‡ Main drug effect (p<0.05) * Significantly greater than SED+DOX

Figure 2

MyoD expression in the soleus (A), extensor digitorum longus (B), and diaphragm (C). Data are mean ± SEM. SED, sedentary; EXER, treadmill exercise trained; SAL, saline injection; DOX; doxorubicin injection. ‡ Main drug effect (p<0.05)

Figure 3

Mrf4 expression in the soleus (A), extensor digitorum longus (B), and diaphragm (C). Data are mean ± SEM. SED, sedentary; EXER, treadmill exercise trained; SAL, saline injection; DOX; doxorubicin injection. † Main exercise effect (p<0.05)

Figure 4

Myogenin expression in the soleus (A), extensor digitorum longus (B), and diaphragm (C). Data are mean ± SEM. SED, sedentary; EXER, treadmill exercise trained; SAL, saline injection; DOX; doxorubicin injection. No significant main effects or differences (p>0.05).