Project 8

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.

For References click here


Project related Publications

Leitner, L. M. , Wilson, R. J., Yan, Z. , and Gödecke, A. (2017) Reactive Oxygen Species/Nitric Oxide Mediated Inter-Organ Communication in Skeletal Muscle Wasting Diseases. Antioxid Redox Signal doi: 10.1089/ars.2016.6942



  1. Evans, W. J., Morley, J. E., Argiles, J., Bales, C., Baracos, V., Guttridge, D., Jatoi,
    A., Kalantar-Zadeh, K., Lochs, H., Mantovani, G., Marks, D., Mitch, W. E., Muscaritoli, M.,
    Najand, A., Ponikowski, P., Rossi Fanelli, F., Schambelan, M., Schols, A., Schuster, M.,
    Thomas, D., Wolfe, R., and Anker, S. D. (2008) Cachexia: a new definition. Clin Nutr 27,
  2. Lecker, S. H., Jagoe, R. T., Gilbert, A., Gomes, M., Baracos, V., Bailey, J., Price, S.
    R., Mitch, W. E., and Goldberg, A. L. (2004) Multiple types of skeletal muscle atrophy
    involve a common program of changes in gene expression. FASEB J 18, 39-5
  3. Brink, M., Price, S. R., Chrast, J., Bailey, J. L., Anwar, A., Mitch, W. E., and
    Delafontaine, P. (2001) Angiotensin II Induces Skeletal Muscle Wasting through Enhanced
    Protein Degradation and Down-Regulates Autocrine Insulin-Like Growth Factor I.
    Endocrinology 142, 1489-1496
  4. Breitbart, A., Auger-Messier, M., Molkentin, J. D., and Heineke, J. (2011) Myostatin
    from the heart: local and systemic actions in cardiac failure and muscle wasting. Am J
    Physiol Heart Circ Physiol 300, H1973-1982
  5. Leitner, L. M., Wilson, R. J., Yan, Z., and Godecke, A. (2017) Reactive Oxygen
    Species/Nitric Oxide Mediated Inter-Organ Communication in Skeletal Muscle Wasting
    Diseases. Antioxid Redox Signal doi: 10.1089/ars.2016.6942
  6. Ebadi, M., and Mazurak, V. C. (2014) Evidence and Mechanisms of Fat Depletion in
    Cancer. Nutrients 6, 5280-5297
  7. Ciciliot, S., Rossi, A. C., Dyar, K. A., Blaauw, B., and Schiaffino, S. (2013) Muscle
    type and fiber type specificity in muscle wasting. Int J Bioch Cell Biol 45, 2191-2199
  8. Li, P., Waters, R. E., Redfern, S. I., Zhang, M., Mao, L., Annex, B. H., and Yan, Z.
    (2007) Oxidative phenotype protects myofibers from pathological insults induced by chronic
    heart failure in mice. Am J Pathol 170, 599-608
  9. Okutsu, M., Call, J. A., Lira, V. A., Zhang, M., Donet, J. A., French, B. A., Martin, K.
    S., Peirce-Cottler, S. M., Rembold, C. M., Annex, B. H., and Yan, Z. (2014) Extracellular
    Superoxide Dismutase Ameliorates Skeletal Muscle Abnormalities, Cachexia and Exercise
    Intolerance in Mice with Congestive Heart Failure. Circ Heart Fail 7, 519-530
  10. Kumar, A., Lawrence, J. C., Jr., Jung, D. Y., Ko, H. J., Keller, S. R., Kim, J. K.,
    Magnuson, M. A., and Harris, T. E. (2010) Fat cell-specific ablation of rictor in mice impairs
    insulin-regulated fat cell and whole-body glucose and lipid metabolism. Diabetes 59, 1397-
  11. Mullins, G. R., Wang, L., Raje, V., Sherwood, S. G., Grande, R. C., Boroda, S.,
    Eaton, J. M., Blancquaert, S., Roger, P. P., Leitinger, N., and Harris, T. E. (2014)
    Catecholamine-induced lipolysis causes mTOR complex dissociation and inhibits glucose
    uptake in adipocytes. Proc Natl Acad Sci U S A 111, 17450-17455
  12. Bottermann, K., Reinartz, M., Barsoum, M., Kotter, S., and Godecke, A. (2013)
    Systematic Analysis Reveals Elongation Factor 2 and alpha-Enolase as Novel Interaction
    Partners of AKT2. PloS one 8, e66045
  13. Moellendorf, S., Kessels, C., Peiseler, L., Raupach, A., Jacoby, C., Vogt, N.,
    Lindecke, A., Koch, L., Bruning, J., Heger, J., Kohrer, K., and Godecke, A. (2012) IGF-IR
    signaling attenuates the age-related decline of diastolic cardiac function. Am J Physiol
    Endocrinol Metab 303, E213-222
  14. Reinartz, M., Raupach, A., Kaisers, W., and Godecke, A. (2014) AKT1 and AKT2
    induce distinct phosphorylation patterns in HL-1 cardiac myocytes. J Proteome Res 13,

Prof. Dr. rer. nat. Axel Gödecke

Department of Cardiovascular Physiology

Prof. Dr. Thurl E. Harris

Department of Pharmacology

Associate Professor Zhen Yan PhD

CVRC, Dept. of Medicine Cardiovascular Medicine

Doctoral Researcher

Lisa Kalfhues M.Sc.


Dr. rer. nat. Vici Oenarto

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