Low-level laser prevents doxorubicin-induced skeletal muscle atrophy by modulating AMPK/SIRT1/PCG-1α-mediated mitochondrial function, apoptosis and up-regulation of pro-inflammatory responses

Hsiu-Chung Ou; Pei-Ming Chu; Yu-Ting Huang; Hui-Ching Cheng; Wan-Ching Chou; Hsin-Lun Yang; Hsiu-I Chen; Kun-Ling Tsai

doi:10.1186/s13578-021-00719-w

Low-level laser prevents doxorubicin-induced skeletal muscle atrophy by modulating AMPK/SIRT1/PCG-1α-mediated mitochondrial function, apoptosis and up-regulation of pro-inflammatory responses

Cell Biosci. 2021 Dec 7;11(1):200. doi: 10.1186/s13578-021-00719-w.

Authors

Hsiu-Chung Ou^#¹, Pei-Ming Chu^#², Yu-Ting Huang³, Hui-Ching Cheng³, Wan-Ching Chou³, Hsin-Lun Yang^{3

4}, Hsiu-I Chen^{1

5}, Kun-Ling Tsai^{6

7}

Affiliations

¹ Department of Physical Therapy, College of Medical and Health Science, Asia University, Taichung, Taiwan, ROC.
² Department of Anatomy, School of Medicine, China Medical University, Taichung, Taiwan, ROC.
³ Department of Physical Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
⁴ Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
⁵ Department of Physical Therapy, Hungkuang University, Taichung, Taiwan, ROC.
⁶ Department of Physical Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC. kunlingtsai@mail.ncku.edu.tw.
⁷ Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC. kunlingtsai@mail.ncku.edu.tw.

^# Contributed equally.

Abstract

Background: 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. 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.

Results: The 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.

Conclusion: Our findings may provide a novel adjuvant intervention that can potentially benefit cancer patients from Dox-induced muscle wasting.

Keywords: AMPK; Doxorubicin; Low-level laser; Myopathy; ROS.

Grants and funding

MOST-1 09-2635-B-468-0013/Ministry of Science and Technology, Taiwan