Fatigue mechanisms and skeletal muscle function in experimental and human heart failure

Abstract

Skeletal muscle fatigue, the decline in skeletal muscle performance with activity, is extensively reviewed in the literature. The common experimental setup is to stimulate a skeletal muscle preparation isometrically and meassure force. The decline in force serves as the fatigue parameter, and muscle from animals with heart failure typically has a greater fall in force than muscle from control animals. Also, skeletal muscle fatigue is a common symptom for the heart failure (chf) patient. This was the basis for the work presented in this thesis in muscle physiology. In spite the great amount of research on skeletel muscle fatigue, only rarely is fatigue studied using shortening contractions. Also, although altered calcium cycling could contribute to the development of fatigue, the calcium handling properties in skeletal muscle from chf patients has not been evaluated. The aim of this thesis is to investigate the development of and the mechanisms contributing to fatigue following shortening contractions. Also, it aims to uncover wheather the increased fatiguability in the chf patient can be explained by altered calcium homeostasis compared to controls. The animals used in this thesis were either healthy or they suffered from chf induced by coronary infarction. All animals were used in an in situ stimulation protocol were the stimulated muscle were allowed to shorten. Muscle biopsies from the thigh were obtained from heart failure patients and healthy contols. The main results are that the ability to shorten seems to be more fatigue sensitive following shortening contractions compared to maximal isometric force capacity and that modification of key proteins in the contractile apparatus could be of importance to the fatigue development. Further, skeletal muscle from chf patients have altered calcium handling properties compared to healthy controls although this seem unrelated to the increased fatiguability in human heart failure.