Transgenic models of cardiac cachexia and cardiac effects of muscular atrophy

Background and aims: Cachexia is a common feature of heart failure and is associated with poor prognosis, increased mortality, unfavourable response to treatment and poor quality of life. Moreover, evidences indicate that cachexia itself has cardiac implications. Because of the difficulties in generating clinical trials for cardiac cachexia, well-characterized animal models are needed to explore the aetiological flow from triggers to disease. This could enable clinicians to identify new therapeutically targetable entities. Methods: The Hepatocyte Growth Factor and its tyrosine-kinase receptor c-Met are involved in many physio-pathological processes, including heart and skeletal muscle growth. To investigate the effects of a sustained activation of Met signalling, we generated two transgenic mouse models with tetracycline-suppressible expression of Tpr-Met, the constitutively active form of Met. Tpr-Met expression was addressed specifically to cardiac or skeletal muscle, by means of αMHC and MCK promoters, respectively. Results: αMHC-Tpr-Met mice revealed as a model of heart failure with early exordium and high penetrance: these mice develop a concentric hypertrophy, which rapidly progresses into congestive heart failure and cardiac cachexia. Cardiac and skeletal muscles from cachectic mice were analysed, and altered pathways/candidate messenger mediators secreted by the heart were highlighted, which could contribute to muscle wasting. Notably, the suppression of Tpr-Met expression and downstream signalling reversed cardiac hypertrophy and prevented the cachectic outcome. Next, with MCK-Tpr-Met mice, we generated a transgenic model of skeletal muscle wasting, which also shows atrophy of the cardiac muscle. Conclusions: Congestive heart failure and cachexia may be linked by a reciprocal causal relationship. The study of αMHC/MCK-Tpr-Met transgenic models might be useful for the identification of molecules responsible for heart-to-skeletal muscle cross-talk and vice versa; indeed, identifying early targets for therapeutic intervention against this pathogenic loop is a fundamental goal to delay wasting.