Research Article: Disruption of MEF2C signaling and loss of sarcomeric and mitochondrial integrity in cancer-induced skeletal muscle wasting

Date Published: February 21, 2012

Publisher: Impact Journals LLC

Author(s): Angie M. Y. Shum, Theodore Mahendradatta, Ryland J. Taylor, Arran B. Painter, Melissa M. Moore, Maria Tsoli, Timothy C. Tan, Stephen J. Clarke, Graham R. Robertson, Patsie Polly.

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Abstract

Cancer cachexia is a highly debilitating paraneoplastic disease observed in more than 50% of patients with advanced cancers and directly contributes to 20% of cancer deaths. Loss of skeletal muscle is a defining characteristic of patients with cancer cachexia and is associated with poor survival. The present study reveals the involvement of a myogenic transcription factor Myocyte Enhancer Factor (MEF) 2C in cancer-induced skeletal muscle wasting. Increased skeletal muscle mRNA expression of Suppressor of Cytokine Signaling (Socs) 3 and the IL-6 receptor indicative of active IL-6 signaling was seen in skeletal muscle of mice bearing the Colon 26 (C26) carcinoma. Loss of skeletal muscle structural integrity and distorted mitochondria were also observed using electron microscopy. Gene and protein expression of MEF2C was significantly downregulated in skeletal muscle from C26-bearing mice. MEF2C gene targets myozenin and myoglobin as well as myokinase were also altered during cachexia, suggesting dysregulated oxygen transport capacity and ATP regeneration in addition to distorted structural integrity. In addition, reduced expression of calcineurin was observed which suggested a potential pathway of MEF2C dysregulation. Together, these effects may limit sarcomeric contractile ability and also predispose skeletal muscle to structural instability; associated with muscle wasting and fatigue in cachexia.

Partial Text

Cachexia is a hypermetabolic wasting syndrome involving the progressive depletion of adipose tissue and skeletal muscle mass, irrespective of nutritional intake. It has the highest incidence in patients with gastrointestinal and pancreatic cancers (83-87%) [1]. At least 20% of cancer deaths are directly caused by cachexia [1]. Cachexia is associated with severe weight loss, muscle wasting, weakness and fatigue and causes psychosocial distress and dependency upon others; significantly impairing quality of life [2]. Importantly, reversal of weight loss has been shown to be associated with increased longevity in tumor-bearing (TB) mice [3]. Therefore, a better understanding of the molecular process underlying skeletal muscle wasting due to cancer cachexia is critical in designing intervention strategies; beneficing both the quality and longevity of cachectic patients.

The data presented in this study provide further insights into the molecular basis of muscle wasting due to cancer cachexia and highlight the potential role of MEF2C in the development of cachexia. A novel observation of dysregulated myogenic gene expression and associated ultrastructural mitochondrial and sarcomeric changes in the C26 mouse model of can cachexia suggests compromised energy homeostasis and sarcomeric integrity in skeletal muscle during cancer cachexia. These effects during the course of disease progression may be related to altered muscle properties such as weakness and fatigue.

 

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