Regulatory Role of the Transcription Factor Twist1 in Cancer-Associated Muscle Cachexia.

Mohammed S Razzaque,Azeddine Atfi

doi:10.3389/fphys.2020.00662

Abstract

Muscle cachexia is a catabolic response, usually takes place in various fatal diseases, such as sepsis, burn injury, and chronic kidney disease. Muscle cachexia is also a common co-morbidity seen in the vast majority of advanced cancer patients, often associated with low quality of life and death due to general organ dysfunction. The triggering events and underlying molecular mechanisms of muscle wasting are not yet clearly defined. Our recent study has shown that the ectopic expression of Twist1 in muscle progenitor cells is sufficient to drive muscle structural protein breakdown and attendant muscle atrophy, reminiscent of muscle cachexia. Intriguingly, muscle Twist1 expression is highly induced in cachectic muscles from several mouse models of pancreatic ductal adenocarcinoma (PDAC), raising the interesting possibility that Twist1 may mediate PDAC-driven muscle cachexia. Along these lines, both genetic and pharmacological inactivation of Twist1 function was highly significant at protecting against cancer cachexia, which translated into a significant survival benefit in the experimental PDAC animals. From a translational perspective, elevated expression of Twist1 is also detected in cancer patients with severe muscle wasting, implicating a role of Twist1 in cancer cachexia, and further providing a possible target for therapeutic attenuation of cachexia to improve cancer patient survival. In this article, we will briefly summarize how Twist1 acts as a master regulator of tumor-induced cachexia, and discuss the relevance of our findings to muscle wasting diseases in general. The mechanism of decreased muscle mass in various catabolic conditions is thought to rely on similar pathways, and, therefore, Twist1-induced cancer cachexia may benefit diverse groups of patients with clinical complications associated with loss of muscle mass and functions, beyond the expected benefits for cancer patients.

Highlights

Cachexia, a hypercatabolic state, is a commonly encountered adverse effect of cancer, and markedly impairs the quality of life by harmfully impacting both the physical and psychosocial behaviors
Our recent studies suggest that the transcription factor twist family bHLH transcription factor 1 (Twist1) is actively involved in the regulation of cancerinduced muscle wasting presumably owing to its ability to induce the expression of muscle RING finger 1 (MuRF1) and Atrogin1, thereby causing muscle protein degradation and attendant muscle cachexia (Parajuli et al, 2018)
Our studies have shown that tumor-derived Activin A acts on the muscle to upregulate the expression of Twist1, which in turn induces the synthesis of the muscle-specific ubiquitin ligases, MuRF1 and Atrogin1, thereby causing muscle cachexia by facilitating muscle protein degradation (Figure 1; Parajuli et al, 2018)

Summary

Introduction

A hypercatabolic state, is a commonly encountered adverse effect of cancer, and markedly impairs the quality of life by harmfully impacting both the physical and psychosocial behaviors. Our recent studies suggest that the transcription factor Twist1 is actively involved in the regulation of cancerinduced muscle wasting presumably owing to its ability to induce the expression of MuRF1 and Atrogin1, thereby causing muscle protein degradation and attendant muscle cachexia (Parajuli et al, 2018). Of particular clinical importance, developing effective treatments to curb cachexia and muscle wasting disorders are essential for improving the quality of health and survival of the cancer patients and beyond.

Results

Conclusion