Oral Resveratrol Therapy Inhibits Cancer-Induced Skeletal Muscle and Cardiac Atrophy In Vivo

Abstract

The mechanism by which cancer mediates muscle atrophy has been delineated in the past 3 decades, and includes a prominent role of tumor-derived cytokines, such as IL-6, TNFα and IL-1. These cytokines interact with their cognate receptors on muscle to activate the downstream transcription factor NF-κB and induce sarcomere proteolysis. Experimentally, inhibiting NF-κB signaling largely prevents cancer-induced muscle wasting, indicating its prominent role in muscle atrophy. Resveratrol, a natural phytoalexin found in the skin of grapes, has recently been shown to inhibit NF-κB in cancer cells, which led us to hypothesize that it might have a protective role in cancer cachexia. Therefore, we investigated if daily oral resveratrol could protect against skeletal muscle loss and cardiac atrophy in an established mouse model. We demonstrate resveratrol inhibits skeletal muscle and cardiac atrophy induced by C26 adenocarcinoma tumors through its inhibition of NF-κB (p65) activity in the skeletal muscle and heart. These studies demonstrate for the first time the utility of oral resveratrol therapy to provide clinical benefit in cancer-induced atrophy through the inhibition of NF-κB in muscle. These findings may have application in the treatment of diseases with parallel pathophysiologies such as muscular dystrophy and heart failure.

Ubiquinol Reduces Muscle Wasting but Not Fatigue in Tumor-Bearing Mice

“…By Days 18–19 of tumor growth, gastrocnemius muscle mass was 20% less and body weight was 5% less in tumor-bearing animals than in healthy control animals, confirming the targeted effect of tumor growth on lean body mass (Martin et al, 2013). These changes in body and gastrocnemius muscle weight were not due to anorexia–cachexia syndrome, as food and water intake of the tumor-bearing animals did not decline during the study period, a finding supported by previous reports (Graves et al, 2006; Shadfar et al, 2011; Xu et al, 2011). However, others have observed reduced food intake and up to 20% body weight loss in this mouse model of tumor-induced muscle wasting (Murphy et al, 2012; Tian et al, 2010).…”

“…This tumor cell line secretes interleukin 6 (IL-6) and TNF-α (Graves, Ramsay, & McCarthy, 2006) and does not metastasize when injected subcutaneously (Okayama et al, 2009). It is frequently used to model the systemic effects of tumor growth on skeletal muscle, heart, gut, and skin (Cosper & Leinwand, 2011; Murphy, Chee, Trieu, Naim, & Lynch, 2012; Redon et al, 2010; Shadfar et al, 2011; Tian et al, 2011). The gastrocnemius is most often used to study the effects of tumor growth on skeletal muscle because it contains both slow- and fast-twitch fibers.…”

Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms of action

“…In addition, resveratrol has shown its protective effect on muscle wasting under diverse catabolic conditions including cachexia and disuse [48,49,53]. Besides this, resveratrol treatment shows its anti-cachectic role by inhibiting NFB activity and MuRF1 expression in MAC16 tumor and C26 adenocarcinoma bearing mice [54,55]. Studies have shown that resveratrol regulates TNF␣ induced atrophy by up-regulating the phosphorylation of Akt, p70S6K, mTOR and 4E-BP1 and protects the dexamethasone-induced atrophy by inhibiting the increase in atrogin1 and MuRF1 expression via activation of SIRT1 (sirtuin, a histone deacetylase) and PGC-1␣ [48,49].…”

“…Studies have shown that resveratrol regulates TNF␣ induced atrophy by up-regulating the phosphorylation of Akt, p70S6K, mTOR and 4E-BP1 and protects the dexamethasone-induced atrophy by inhibiting the increase in atrogin1 and MuRF1 expression via activation of SIRT1 (sirtuin, a histone deacetylase) and PGC-1␣ [48,49]. In streptozotocin induced diabetic rat model, resveratrol administration enhanced the insulin sensitivity, AMP-activated protein kinase (AMPK) and SIRT1 activities, and mitochondrial genesis and down-regulated the mRNA expression of pro-inflammatory cytokines (IL-1␤ and IL-6) and NFB expression [52,55]. Furthermore, resveratrol treatment for COPD decreases the levels of TNF␣ and increases the expression of SIRT1 which ultimately activates AMPK and regulates the muscle wasting [56].…”

F-BOX proteins in cancer cachexia and muscle wasting: Emerging regulators and therapeutic opportunities

“…Earliest evidence came from cardiac models in which resveratrol was shown to prevent atrophy through the inhibition of NF-κB (p65) [103,104]. Guided by these initial findings a number of newer investigations have shed light on the multi-faceted effects of resveratrol on muscle wasting genes.…”