Linalool Prevents Cisplatin Induced Muscle Atrophy by Regulating IGF-1/Akt/FoxO Pathway

Abstract

Skeletal muscle atrophy is an important feature of cancer cachexia, which can be induced by chemotherapy, and affects the survival and quality of life of cancer patients seriously. No specific drugs for cancer cachexia have been applied in clinical practice. This study explored the therapeutic effect of linalool (LIN) on cisplatin (DDP) induced skeletal muscle atrophy. In vivo, LIN can improve skeletal muscle weight loss, anorexia, muscle strength decline and other cachexia symptoms caused by cisplatin treatment in a Lewis lung cancer tumor bearing mouse model, and cause no adverse effects on the anti-tumour effect. LIN treatment decreased the expression of muscle RING-finger protein-1 (MuRF1) and Atrogin1(MAFbx) in muscle, and the activation of insulin-like growth factor-1 (IGF-1)/protein kinase B (Akt)/forkhead box O (FoxO) pathway was observed. In vitro, LIN alleviated DDP induced C2C12 myotube atrophy, and IGF-1 receptor inhibitor Picropodophyllin (PIC), which had no adverse effect on C2C12 myotube cells, could reverse the protective effect of LIN. These results indicate that LIN down-regulates the expression of Atrogin1 and MuRF1 through the IGF-1/Akt/FoxO pathway, alleviating DDP-induced muscle atrophy and improving cachexia symptoms. LIN has the potential to be developed as a drug against cancer cachexia.

Daidzein alleviates cisplatin‐induced muscle atrophy by regulating Glut4/AMPK/FoxO pathway

“…In this study, the treatment of DDP did obtain antitumour effect, but it was also accompanied by the occurrence of cachexia. DDP can lead to FoxO mediated skeletal muscle atrophy, which is consistent with previous reports of DDP‐induced skeletal muscle atrophy (Conte et al, 2020; Sakai et al, 2020; Zhang et al, 2020). As a chemotherapeutic drug interacting with DNA, DDP also has antimetabolic effect.…”

“…The diameter of fast‐twitch glycolic fibres was larger than that of slow‐twitch oxic fibres, so the CSA of GA muscle fibres was significantly reduced. Fast‐twitch glycolytic fibres are more vulnerable than slow‐twitch oxidative fibres under a variety of atrophic conditions related to signaling transduction of FoxO family, autophagy inhibition, transforming growth factor‐beta family and NFκB (Wang & Pessin, 2013; Zhang et al, 2020). Different types of muscle fibres express different MyHC, such as MyHC I, MyHC IIA and MyHC IIB encoded by genes MYH7, MYH2 and MYH4 (Schiaffino, 2018).…”

“…In skeletal muscle, DAI prevents the conversion of skeletal muscle fibre types. In the case of DDP intervention or aging, the CSA of type II skeletal muscle fibres will decrease, the proportion of type I skeletal muscle fibres will increase relatively, and the contraction of type II skeletal muscle fibre will significantly reduce the contraction strength of the skeletal muscle (Nilwik et al, 2013; Zhang et al, 2020), DAI intervention maintained the proportion of type II skeletal muscle fibre and alleviated the damage of skeletal muscle strength. DAI up‐regulated the expression of Glut4 and maintained energy supply.…”

“…There is still a lot of work to be done before DAI enters into clinical transformation. DDP‐induced skeletal muscle atrophy is related to a variety of biological processes and signaling pathways, such as IGF/AKT/FoxO pathway, NFκB signaling pathway, p38/C/EBP‐β/myostatin signaling pathway, mTOR/Smads signaling pathway, and so on (Conte et al, 2020; Lee et al, 2020; Sakai et al, 2014; Zhang et al, 2020). Whether the mechanism of DAI is related to these pathways needs to be further explored.…”

Chemotherapy-Induced Myopathy: The Dark Side of the Cachexia Sphere

“…Drug candidates focus on different biochemical targets that are involved in diverse molecular and physiological aspects that characterise the cachectic myopathy phenotype [ 40 ]. These candidates arise from a range of different therapeutic classes including activin receptor signalling inhibitors [ 59 , 60 , 100 , 103 , 165 ], appetite stimulants [ 77 , 80 , 82 , 166 , 167 , 168 , 169 , 170 ], nutritional supplements [ 171 , 172 , 173 , 174 , 175 , 176 ], and phytotherapies [ 112 , 113 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 ]. Activin receptor signalling inhibitors have shown strong pre-clinical efficacy to mitigate cancer and chemotherapy-induced cachexia through preserving skeletal muscle mass and function [ 186 ].…”