The benefit of exercise training on heart rate response in patients with heart failure has been well documented, as well as the exercise intolerance which is developed by patients and that limits the exercise benefit. Several studies showed that a decrease in the exercise tolerance in patients with chronic heart failure (CHF) is a strong prognostic indicator of cardiovascular events. As the life expectancy of patients with heart disease has improved in recent years, a deeper understanding of the molecular causes of exercise intolerance, is of primary scientific, clinical and social importance. Exercise intolerance is defined as the reduced ability to perform daily activities that involve dynamic movement of large skeletal muscles because of symptoms of dyspnea or fatigue. Many investigators have sought mechanisms to explain the source of exercise intolerance. Importantly, hemodynamic improvements do not acutely reverse this process. Therefore, several different lines of evidence have converged to identify skeletal muscle pathology as a major contributor to exercise intolerance. While numerous studies have linked enzymatic and histologic abnormalities to exercise intolerance, the underlying mechanisms driving these processes remain poorly understood. An useful animal model to investigate these aspects at a cellular/molecular level is represented by the Tgαq 44* mice line, a transgenic mice model of CHF resulting from a cardiac-specific overexpression of constitutively active Gαq protein. This model is characterized by a gradual progression of the disease and for this reason offers the great advantage of studying muscle adaptations from the early to the late stage of the disease. Furthermore, voluntary exercise represents a training modality in which physical activity occurs under non-stressful conditions representing a valid training intervention to assess the presence of exercise intolerance. The major findings of this thesis can be divided in (i) the characterization of the muscle alterations in skeletal muscle in mice with dilated cardiomyopathy and (ii) the analysis of how these alterations are related to in vivo functional performance over time. Our results support these observation since a partially recovery of oxidative metabolism i.e. PGC-1α, energy state i.e. AMPK, mitochondrial network i.e DRP1 and Mfn and OXPHOS capacity, was observed in Tg exercised fast muscle. Importantly, the partial recovery of these parametrs to the control value (age-matched FVB), strongly correlated to improvement in functional performance, increasing the exercise tolerance, at all phases of DCM.
|Titolo:||Skeletal muscle deterioration in dilated cardiomyopathy: molecular mechanism and effect of prolonged endurance training in a mice model|
|Data di pubblicazione:||28-feb-2017|
|Appare nelle tipologie:||8.01 Tesi di dottorato|