Does FHL 1 enhanced myostatin activity mediate intensive care unit acquired paresis ?
Lead Research Organisation:
Imperial College London
Department Name: National Heart and Lung Institute
Abstract
Skeletal muscle weakness and wasting is a common complication of critical illness and is associated with a poor outcome and prolonged stay on intensive care units (ICU); this is known as ICU acquired paresis (ICUAP). The causes are not fully understood, but it is thought that many factors contribute, including infection, medications and immobility. FHL1 and myostatin are proteins that are important in the regulation of muscle mass and are themselves regulated by muscle activity. It is not known if they are important in the development of ICUAP in humans but, based on current scientific evidence, we believe that they will be. This project aims to investigate the roles of these proteins and their importance in ICUAP. With experiments in the laboratory and in real patients on ICU we will test our theory that they interact together and are important in the development of ICUAP. With this study we hope to be able to better understand the factors leading to this problem and generate target for potential treatments.
Technical Summary
Our aim is to explore the hypothesis that FHL1 enhances myostatin signalling thereby contributing to ICU acquired paresis (ICUAP). FHL-1 and myostatin have been identified as important regulators of muscle mass and fibre type in many experimental models (including in COPD patients by Prof
Polkey‘s group). Their activity is also known be dependent on muscle activity, denervation and, in
the case of myostatin, corticosteroids - factors which are all thought to be important in the development of ICUAP. The objective of this research is to investigate the potential role of these proteins in the pathogenesis of ICUAP. Recent research has shown that both FHL1 and myostatin interact with SMAD proteins leading to the hypothesis that FHL1 will enhance the atrophic properties of myostatin. We have designed a series of studies to investigate this hypothesis and the effect
of physical activity on these pathways in vitro and in vivo. Using cultured myotubes we aim to demonstrate the relationship between FHL1 and myostatin signalling via the SMAD proteins and determine the effect of activity on these pathways by stretching the cells. In an interventional trial of electrical muscle stimulation in ICU patients we will compare pre- and post-ICU quadriceps biopsies from trained and untrained legs. This will enable us to determine the effect of inactivity and ICU insults on these pathways and the effect of increased physical activity. We will also conduct a cross-sectional study of patients with and without ICUAP. ICUAP is a common problem affecting up to 30% of all critically ill patients and is known to be associated with poor outcomes and prolonged length of stay in ICU. A greater understanding of the pathogenesis of this disease and the identification of potential targets for treatment provide the opportunity to significantly improve human health.
Polkey‘s group). Their activity is also known be dependent on muscle activity, denervation and, in
the case of myostatin, corticosteroids - factors which are all thought to be important in the development of ICUAP. The objective of this research is to investigate the potential role of these proteins in the pathogenesis of ICUAP. Recent research has shown that both FHL1 and myostatin interact with SMAD proteins leading to the hypothesis that FHL1 will enhance the atrophic properties of myostatin. We have designed a series of studies to investigate this hypothesis and the effect
of physical activity on these pathways in vitro and in vivo. Using cultured myotubes we aim to demonstrate the relationship between FHL1 and myostatin signalling via the SMAD proteins and determine the effect of activity on these pathways by stretching the cells. In an interventional trial of electrical muscle stimulation in ICU patients we will compare pre- and post-ICU quadriceps biopsies from trained and untrained legs. This will enable us to determine the effect of inactivity and ICU insults on these pathways and the effect of increased physical activity. We will also conduct a cross-sectional study of patients with and without ICUAP. ICUAP is a common problem affecting up to 30% of all critically ill patients and is known to be associated with poor outcomes and prolonged length of stay in ICU. A greater understanding of the pathogenesis of this disease and the identification of potential targets for treatment provide the opportunity to significantly improve human health.