Cellular mechanisms of human muscle fatigue and disease-related loss of muscle function

Abstract

A loss of skeletal muscle function and mass is a hallmark of several diseases resulting in a dismal life quality and poor prognosis. Impaired intracellular Ca2+-handling has been proposed as an underlying cause of these manifestations. This thesis investigated the cellular mechanisms of human muscle fatigue and disease-related loss of muscle function and mass. Special focus was put on the contribution of altered intracellular Ca2+-handling to these processes. The thesis makes three main contributions by: (i) providing mechanistic insight into the underlying causes of fatigue in human muscle fibres, (ii) elucidating the direct effects of vitamin D in human muscle, and (iii) implicating sphingomyelinase (SMase) activation in disease-related loss of muscle function and mass.

Study I examined single intact muscle fibres and differentiated muscle stem cells (myotubes) as experimental models of human skeletal muscle. Results revealed that single intact fibres could be manually dissected, enabling studies of Ca2+-regulated processes and force generation. Major differences in intracellular Ca2+-handling between myotubes and muscle fibres were discerned. In study II, the effects of vitamin D in human skeletal muscle were investigated. Data demonstrated a modulatory role of vitamin D on muscle stem cells, but did not support presence of the vitamin D receptor in muscle fibres. In study III, the cellular mechanisms of fatigue were examined in single intact fibres. Fatigue-induced force loss was caused by a reduction in sarcoplasmic reticulum (SR) Ca2+ release, while a decrease in myofibrillar Ca2+ sensitivity played no role. Acidification did not reduce force production or fatigue tolerance of human fibres. Study IV investigated the tentative role of SMase in disease-related muscle weakness and atrophy. SMase produced a prompt force decline by a reduction in SR Ca2+ release and decreased myofibrillar Ca2+ sensitivity, while promoting atrophy processes. Intramuscular SMase activity was elevated in heart failure compared to control individuals, and positively correlated with circulating markers of inflammation and atrophy, and with factors carrying prognostic value.

This thesis reveals differences in the intracellular Ca2+-handling properties of myotubes and muscle fibres, and in the underlying causes of fatigue in humans and animals. This warrants caution when transferring findings in animal fibres and human myotubes to the situation in human skeletal muscle. The effects of vitamin D on muscle stem cells suggest an importance of vitamin D in skeletal muscle health. This should be considered in conditions of severe vitamin D deficiency, e.g. chronic kidney disease. Results implicate elevated SMase activity in the advent of muscle weakness and atrophy, suggesting SMase as a tentative target for therapeutic interventions in diseases associated with a loss of skeletal muscle function and mass.