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Lysosomal, cytoskeletal, and metabolic alterations in cardiomyopathy of cathepsin L knockout mice

Ivonne Petermann^*,1, Christian Mayer^*,1, Jörg Stypmann, Martin L. Biniossek^*, Desmond J. Tobin, Markus A. Engelen, Thomas Dandekar, Tilman Grune^||, Lorenz Schild^¶, Christoph Peters^*,2 and Thomas Reinheckel^*

^* Institut für Molekulare Medizin und Zellforschung, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany;

Medizinische Klinik und Poliklinik C (Kardiologie und Angiologie), Zentrale Projektgruppe Kleintierdiagnostik des Interdisziplinären Zentrums für Klinische Forschung Münster, Universitätsklinikum Westfälische Wilhelms-Universität Münster, Münster, Germany;

Medical Biosciences, School of Life Sciences, University of Bradford, Bradford, West Yorkshire, UK;

Lehrstuhl für Bioinformatik, Biozentrum, Am Hubland, Würzburg, Germany;

^|| Research Institute for Environmental Medicine at the Heinrich Heine University Duesseldorf, Molecular Aging Research, Duesseldorf, Germany; and

^¶ Institut für Klinische Chemie und Pathologische Biochemie, Bereich Pathologische Biochemie, Medizinische Fakultät der Otto-von-Guericke-Universität Magdeburg, Germany

²Correspondence: Institut für Molekulare Medizin und Zellforschung, Albert-Ludwigs-Universität Freiburg, Freiburg D-79104, Germany. E-mail: christoph.peters{at}mol-med.uni.freiburg-de

ABSTRACT

Although lysosomal proteases are expressed in the heart at considerable levels, their specific functions in this organ remain elusive. Mice deficient for the lysosomal cysteine protease cathepsin L (CTSL) develop a late onset dilated cardiomyopathy (DCM) that is characterized by cardiac chamber dilation, fibrosis, and impaired cardiac contraction at 12 month of age. Investigation of the pathogenic sequence of DCM in ctsl^–/– mice revealed numerous dysmorphic lysosome-like structures in heart muscle as early as 3 days after birth, whereas skeletal muscle was not affected. Labeling of the acidic cell compartment of neonatal cardiomyocytes and detection of lysosomal markers after subcellular fractionation confirmed increased lysosome content in CTSL deficient myocardium; however, specific storage materials were not detected. The myocardium of ctsl^+/+ and ctsl^–/– mice revealed no differences in incidence of cell death, proliferation, and capillary density during DCM progression. However, an observed increase in mRNA expression of natriuretic peptides in young adult mice indicates the activation of the adaptive "fetal" gene program, while proteome analysis revealed decreased levels of the sarcomere-associated proteins -tropomyosin, desmin, and calsarcin 1, as well as considerable changes of metabolic enzymes. Bioinformatic pathway analysis suggested a switch to anaerobic catabolism and impairment of mitochondrial respiration. This interpretation was supported by a 50% reduction in resting state oxygen consumption and impaired respiration capacity in ctsl^–/– myocardial homogenates. In summary, the data indicate an essential role of CTSL in maintaining the structure of the endosomal/lysosomal compartment in cardiomyocytes. Lysosomal impairment in ctsl^–/– hearts results in metabolic and sarcomeric alterations that promote DCM development.—Petermann, I., Mayer, C., Stypmann, J., Biniossek, M. L., Tobin, D. J., Engelen, M. A., Dandekar, T., Grune, T., Schild, L., Peters, C., Reinheckel, T. Lysosomal, cytoskeletal, and metabolic alterations in cardiomyopathy of cathepsin L knockout mice.

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