A New Transgenic Mouse Model of Heart Failure and Cardiac Cachexia Raised by Sustained Activation of Met Tyrosine Kinase in the Heart.
Among other diseases characterized by the onset of cachexia, congestive heart failure takes a place of relevance, considering the high prevalence of this pathology in most European countries and in the United States, and is undergoing a rapid increase in developing countries. Actually, only few models of cardiac cachexia exist. Difficulties in the recruitment and follow-up of clinical trials implicate that new reproducible and well-characterized animal models are pivotal in developing therapeutic strategies for cachexia. We generated a new model of cardiac cachexia: a transgenic mouse expressing Tpr-Met receptor, the activated form of c-Met receptor of hepatocyte growth factor, specifically in the heart. We showed that the cardiac-specific induction of Tpr-Met raises a cardiac hypertrophic remodelling, which progresses into concentric hypertrophy with concomitant increase in Gdf15 mRNA levels. Hypertrophy progresses to congestive heart failure with preserved ejection fraction, characterized by reduced body weight gain and food intake and skeletal muscle wasting. Prevention trial by suppressing Tpr-Met showed that loss of body weight could be prevented. Skeletal muscle wasting was also associated with altered gene expression profiling. We propose transgenic Tpr-Met mice as a new model of cardiac cachexia, which will constitute a powerful tool to understand such complex pathology and test new drugs/approaches at the preclinical level.
Department of Oncology, University of Turin, 10126 Turin, Italy; Department of Medical Sciences, University of Turin, 10126 Turin, Italy.
Valentina
V
Sala
Department of Oncology, University of Turin, 10126 Turin, Italy.
Stefano
S
Gatti
Department of Oncology, University of Turin, 10126 Turin, Italy.
Simona
S
Gallo
Department of Oncology, University of Turin, 10126 Turin, Italy; FPO-IRCCS, 10060 Candiolo, Italy.
Enzo
E
Medico
FPO-IRCCS, 10060 Candiolo, Italy.
Daniela
D
Cantarella
Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy.
James
J
Cimino
Department of Medical Sciences, University of Turin, 10126 Turin, Italy.
Antonio
A
Ponzetto
Department of Oncology, University of Turin, 10126 Turin, Italy.
Tiziana
T
Crepaldi
D000818:Animals; D002100:Cachexia / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006333:Heart Failure / Q000150:complications* / Q000175:diagnosis / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D050490:Oncogene Protein tpr-met / Q000235:genetics* / Q000378:metabolism
D050490:Oncogene Protein tpr-met