Photobiomodulation therapy moderates cancer cachexia-associated muscle wasting through activating PI3K/AKT/FoxO3a pathway

Cancer cachexia-associated muscle wasting as a multifactorial wasting syndrome, is an important factor affecting the long-term survival rate of tumor patients. Photobiomodulation therapy (PBMT) has emerged as a promising tool to cure and prevent many diseases. However, the effect of PBMT on skeletal muscle atrophy during cancer progression has not been fully demonstrated yet. Here, we found PBMT alleviated the atrophy of myotube diameter induced by cancer cells in vitro, and prevented cancer-associated muscle atrophy in mice bearing tumor. Mechanistically, the alleviation of muscle wasting by PBMT was found to be involved in inhibiting E3 ubiquitin ligases MAFbx and MuRF-1. In addition, transcriptomic analysis using RNA-seq and GSEA revealed that PI3K/AKT pathway might be involved in PBMT-prevented muscle cachexia. Next, we showed the protective effect of PBMT against muscle cachexia was totally blocked by AKT inhibitor in vitro and in vivo. Moreover, PBMT-activated AKT promoted FoxO3a phosphorylation and thus inhibiting the nucleus entry of FoxO3a. Lastly, in cisplatin-treated muscle cachexia model, PBMT had also been shown to ameliorate muscle atrophy through enhancing PI3K/AKT pathway to suppress MAFbx and MuRF-1 expression. These novel findings revealed that PBMT could be a promising therapeutic approach in treating muscle cachexia induced by cancer.

Schematic representation of the signaling pathway for PBM therapy ameliorates cancer cachexia-associated muscle wasting. In cancer cachexia mice, myostatin and activin released by tumor cells act on the corresponding receptor ActRIIB by vascular transportation. Subsequent Smad2/3 are phosphorylated to reduce AKT activity and suppress FoxO3a phosphorylation. Dephosphorylated FoxO3a are translocated into the nucleus and induce the transcription of target genes (MAFbx and MuRF-1) which regulate the ubiquitin–proteasome systems, resulting in muscle wasting. After receiving PBM therapy, PI3K-AKT signaling is activated, and then stimulates protein synthesis by activating mTOR. mTOR activates the P70S6K, leading to protein synthesis. AKT also phosphorylates and inhibits the nucleus entry of FoxO3a, thereby alleviating muscle wasting.