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P8: Heart - adipose tissue - skeletal muscle interactions in heart failure

Current state of relevant research

Chronic disease, such as cancer, heart failure, kidney disease, COPD, or AIDS cause wasting of skeletal muscle and adipose tissue, a disease state called cachexia. Clinical features of cachexia include weight loss, anorexia, inflammation, insulin resistance, etc. In particular, muscle wasting plays an important role in cachectic patients (1), as it is mainly responsible for the weight loss, weakness and fatigue of patients. Apparently, the diseased organs secrete soluble factors, which induce in skeletal muscle a set of genes called atrogenes (2), which induce the ubiquitin-proteasome system, leading to protein degradation. Moreover, elevated ROS levels due to modulation of NADPH oxidases and mitochondrial function contribute to disease progression. Angiotensin II and growth factors of the TGFβ family (e.g. myostatin) seem to be involved in the induction of muscle wasting (3, 4). Besides activation of the ubiquitin–proteasome pathway the autophagy/lysosomal proteolytic pathway may be involved but its causal role in development of muscle wasting remains controversial (5). In adipose tissue, enhanced lipolysis and browning have been associated with cancer cachexia, however, in particular the contribution of the latter point has not been understood in the context of cardiac cachexia (6).

Preliminary work 

During the first funding period we have identified a novel mouse model of cardiac cachexia. Cardiac myocyte-specific deletion of p38MAPKα (iCMp38MAPKα KO) results in a rapid left-ventricular dilatation when the heart is mechanically stressed due to increased afterload. This dilatation is associated with a loss of metabolic flexibility characterized by lipid droplet deposition in CM, loss of insulin-sensitivity and a substantial infiltration of neutrophils, which migrate specifically to sites of lipid droplet formation. Depletion of neutrophils did not prevent lipid accumulation but led to a partial functional recovery of mice. These findings indicate that lipid accumulation is causal for neutrophil infiltration.

Moreover, we have found, that cardiac dysfunction is associated with a substantial alteration of the gene expression program in M.plantaris, a type II fiber-rich muscle. Notably, we found as early as two days after induction of LV dilation a strong activation of atrogenes in M. plantaris but only a weak one in M. soleus. This fiber-type preference is similar to human patients of cachexia (7). Thus, this model develops important features of a cachectic phenotype and appears to be suitable for investigation of early stimuli altering skeletal muscle gene expression.

Research objectives of the joint program

The combination of the groups of Harris, Yan, and Gödecke aims to concentrate important experimental expertise to investigate the tissues mainly affected by cachexia, i.e. adipose tissue (Harris), skeletal muscle (Yan) and heart (Gödecke). The Yan lab focusses on mechanisms of endurance vs. resistance exercise on muscle wasting disorders (8, 9). Recently, Prof. Yan constructed a unique setup for quantifiable resistance or endurance training for mice, which for the first time allows to study the effect of one or the other training in mice. The expertise of Prof. Harris lies in the field of adipose tissue function and insulin signaling (10, 11). He brings in broad experience in MS based analysis of lipids/ fatty acids, which is of high importance for the aim to study wasting of adipose tissue and skeletal muscle in heart failure. The Gödecke lab has established p38MAPKα KO mice as novel model for heart failure associated wasting disease, which is central for the combined analysis. Moreover, this group will provide functional analysis and proteomic analysis (12-15) for identification of the cardiac secretome as well as reporter cell lines for the analysis of atrogen inducing factors.