Weight Loss in Cancer Patients Correlates With p38β MAPK Activation in Skeletal Muscle.

Guohua Zhang,Yi-Ping Li,Hongyu Wu,Thomas K Sin,Atreya Dash,Peter C Wu,Lindsey J Anderson,Jose M Garcia,Song Gao,Syed H Jafri,Solomon A Graf,Zicheng Zhang

doi:10.3389/fcell.2021.784424

Abstract

Unintentional weight loss, a first clinical sign of muscle wasting, is a major threat to cancer survival without a defined etiology. We previously identified in mice that p38β MAPK mediates cancer-induced muscle wasting by stimulating protein catabolism. However, whether this mechanism is relevant to humans is unknown. In this study, we recruited men with cancer and weight loss (CWL) or weight stable (CWS), and non-cancer controls (NCC), who were consented to rectus abdominis (RA) biopsy and blood sampling (n = 20/group). In the RA of both CWS and CWL, levels of activated p38β MAPK and its effectors in the catabolic pathways were higher than in NCC, with progressively higher active p38β MAPK detected in CWL. Remarkably, levels of active p38β MAPK correlated with weight loss. Plasma analysis for factors that activate p38β MAPK revealed higher levels in some cytokines as well as Hsp70 and Hsp90 in CWS and/or CWL. Thus, p38β MAPK appears a biomarker of weight loss in cancer patients.

Highlights

Unintentional weight loss is a hallmark of cachexia and one of the most challenging aspects of managing cancer patients with no established treatment
Higher active p38β MAPK levels were detected in CWS, which was further increased in cancer and weight loss (CWL) (Figure 1B), suggesting that p38β MAPK is preferentially activated over other members of the p38 MAPK family in cancer patients with weight loss
We examined the levels of active NF-κB and AKT, which are TLR4 effectors (Doyle et al, 2011; Zhang et al, 2017b) and often activated in skeletal muscle of cancer patients (Zhou et al, 2010; Stephens et al, 2015)

Summary

INTRODUCTION

Unintentional weight loss is a hallmark of cachexia and one of the most challenging aspects of managing cancer patients with no established treatment. P38β MAPK activates autophagosome formation by directly phosphorylating ULK1 on its Ser555 residue (Liu et al, 2018) These events lead to increased degradation of muscle proteins such as myosin heavy chain, a target of UPP, and p62, a target of ALP, respectively, resulting in muscle wasting (Liu et al, 2018). Whether circulating Hsp and Hsp elevate in association with p38β MAPK activation in cancer patients with weight loss is unknown. We found that in these cancer patients, higher p38β MAPK activity co-exists with increased catabolic signaling, lower levels of muscle proteins and elevated circulating Hsp and Hsp. A p value smaller than 0.05 is considered significant

RESULTS

DISCUSSION

ETHICS STATEMENT