Exercise training can induce cardiac autophagy at end-stage chronic conditions: insights from a graft-versus-host-disease mouse model.
BACKGROUND
Chronic graft-versus-host disease (cGVHD) is a frequent cause of morbimortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and severely compromises patients' physical capacity. Despite the aggressive nature of the disease, aerobic exercise training can positively impact survival as well as clinical and functional parameters. We analyzed potential mechanisms underlying the recently reported cardiac function improvement in an exercise-trained cGVHD murine model receiving lethal total body irradiation and immunosuppressant treatment (Fiuza-Luces et al., 2013. Med Sci Sports Exerc 45, 1703-1711). We hypothesized that a cellular quality-control mechanism that is receiving growing attention in biomedicine, autophagy, was involved in such improvement.


METHODS
BALB/C female mice (aged 8wk) with cGVHD were randomly assigned to a control/exercise group (n=12/11); the exercise group underwent moderate-intensity treadmill training during 11wk after allo-HSCT. In the hearts of those few mice surviving the entire 11wk period (n=2/5), we studied molecular markers of: macroautophagy induction, preservation of contractile/structural proteins, oxidative capacity, oxidative stress, antioxidant defense, and mitochondrial dynamics.


RESULTS
Mainly, exercise training increased the myocardial content of the macroautophagy markers LC3BII, Atg12, SQSTM1/p62 and phospho-ULK1 (S555), as well as of α-tubuline, catalase and glutathione reductase (all p<0.05).


CONCLUSIONS
Our results suggest that exercise training elicits a positive autophagic adaptation in the myocardium that may help preserve cardiac function even at the end-stage of a devastating disease like cGVHD. These preliminary findings might provide new insights into the cardiac exercise benefits in chronic/debilitating conditions.
European University and Hospital Universitario 12 de Octubre Research Institute (i+12), Madrid, Spain.
Carmen
C
Fiuza-Luces
Mitochondrial and Neuromuscular Diseases Laboratory, Hospital Universitario 12 de Octubre Research Institute (i+12), Madrid, Spain; Spanish Network for Biomedical Research in Rare Diseases (CIBERER), U723, Spain.
Aitor
A
Delmiro
Research Centre in Physical Activity, Health and Leisure, Faculty of Sport, University of Porto, Portugal.
Luisa
L
Soares-Miranda
Children's University Hospital Niño Jesús, Madrid, Spain.
África
Á
González-Murillo
Centre of Energy, Environment and Technical Research (CIEMAT), Madrid, Spain.
Jesús
J
Martínez-Palacios
Children's University Hospital Niño Jesús, Madrid, Spain.
Manuel
M
Ramírez
European University and Hospital Universitario 12 de Octubre Research Institute (i+12), Madrid, Spain.
Alejandro
A
Lucia
Mitochondrial and Neuromuscular Diseases Laboratory, Hospital Universitario 12 de Octubre Research Institute (i+12), Madrid, Spain; Spanish Network for Biomedical Research in Rare Diseases (CIBERER), U723, Spain. Electronic address: mmoran@12o.es.
María
M
Morán
D000818:Animals; D001343:Autophagy; D002908:Chronic Disease; D004195:Disease Models, Animal; D005081:Exercise Therapy; D005260:Female; D006086:Graft vs Host Disease / Q000378:metabolism* / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000378:metabolism*
Autophagosome; Mitochondrial dynamics; ROS; Training