Abstract
BackgroundDoxorubicin (Dox) is a widely used anthracycline drug to treat cancer, yet numerous adverse effects influencing different organs may offset the treatment outcome, which in turn affects the patient’s quality of life. Low-level lasers (LLLs) have resulted in several novel indications in addition to traditional orthopedic conditions, such as increased fatigue resistance and muscle strength. However, the mechanisms by which LLL irradiation exerts beneficial effects on muscle atrophy are still largely unknown.ResultsThe present study aimed to test our hypothesis that LLL irradiation protects skeletal muscles against Dox-induced muscle wasting by using both animal and C2C12 myoblast cell models. We established SD rats treated with 4 consecutive Dox injections (12 mg/kg cumulative dose) and C2C12 myoblast cells incubated with 2 μM Dox to explore the protective effects of LLL irradiation. We found that LLL irradiation markedly alleviated Dox-induced muscle wasting in rats. Additionally, LLL irradiation inhibited Dox-induced mitochondrial dysfunction, apoptosis, and oxidative stress via the activation of AMPK and upregulation of SIRT1 with its downstream signaling PGC-1α. These aforementioned beneficial effects of LLL irradiation were reversed by knockdown AMPK, SIRT1, and PGC-1α in C2C12 cells transfected with siRNA and were negated by cotreatment with mitochondrial antioxidant and P38MAPK inhibitor. Therefore, AMPK/SIRT1/PGC-1α pathway activation may represent a new mechanism by which LLL irradiation exerts protection against Dox myotoxicity through preservation of mitochondrial homeostasis and alleviation of oxidative stress and apoptosis.ConclusionOur findings may provide a novel adjuvant intervention that can potentially benefit cancer patients from Dox-induced muscle wasting.
Highlights
Cancer has been considered one of the top leading causes of mortality worldwide for decades, and pharmacological intervention strategies rely heavenly on chemotherapy to treat cancer patients
Since AMP-activated protein kinase (AMPK) activation plays a crucial role in alleviating mitochondrial oxidative damage in cardiotoxicity caused by Dox [27], we aimed to investigate whether AMPK activation is involved in the protective effects of Lowlevel lasers (LLLs) irradiation by using C2C12, a myoblast cell line
Consistent with prior research that suggested that the activation of AMPK can enhance glucose uptake in isolated skeletal muscles [32] and that Dox-induced muscle atrophy can be attenuated by interventions that can activate the AMPK signaling pathway [33], the findings from the present study suggested that cells exposed to LLL irradiation alone significantly increase the phosphorylation levels of AMPK and reverse Dox-impaired AMPK phosphorylation
Summary
Cancer has been considered one of the top leading causes of mortality worldwide for decades, and pharmacological intervention strategies rely heavenly on chemotherapy to treat cancer patients. Doxorubicin (Dox), an anthracycline antibiotic, has been widely used in the treatment of hematological malignancies and solid tumors for five decades [1]. The antineoplastic effects of Dox are mainly attributed to its properties of interrupting DNA replication as well as RNA transcription. Because of interfering with the synthesis of DNA, RNA, and proteins, the division of cancerous cells is effectively abolished. Cachexia presenting with nausea, fatigue, hair and weight loss, skeletal muscle atrophy, and cardiotoxicity together negatively impact the quality of life of patients when administered systemically. Doxorubicin (Dox) is a widely used anthracycline drug to treat cancer, yet numerous adverse effects influencing different organs may offset the treatment outcome, which in turn affects the patient’s quality of life. The mechanisms by which LLL irradiation exerts beneficial effects on muscle atrophy are still largely unknown
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