Critical illness myopathy : understanding different effects on muscle fibre function

Abstract: Skeletal muscle is an essential component of the human body, being one of the most dynamic and plastic tissues. As such it can be altered by numerous confounding factors. Critical illness myopathy is a common and complex manifestation seen in the intensive care unit and it has over the past decade become an increasing problem that will only escalate further with time. Understanding the processes and underlying mechanisms of muscle regulation with respect to critical illness myopathy is an area of great research focus and aims to improve scientific knowledge and patient care. My thesis has provided further insight into this highly orchestrated process. The overall goal of my PhD project was to investigate the importance of two potential contributors, nutrition and ageing, in the development of muscle fibre dysfunction in response to the intensive care unit condition; critical illness myopathy, and evaluate the efficiency of one potential therapeutic intervention (BGP-15) using a rodent model mimicking the intensive care unit environment. Nutritional feeding of a eucaloric vs low caloric diet was found not to differ in the preferential myosin loss, decline in specific force and muscle fibre atrophy of the limb muscles after a period of controlled mechanical ventilation of up to 14 days. The term “specific force” has been accepted as an indicator of muscle quality and is the generated force by a muscle adjusted for its size. In both experimental groups, passive mechanical loading had a sparing effect of muscle weight independent of nutritional status. We observed in both young and old rats an unexpected response of the diaphragm fibres to 5 days controlled mechanical ventilation, an ineffective compensatory hypertrophy, in conjunction with a decreased maximum force in both age groups compared with controls, resulting in an age related dramatic loss of specific force. Administration of the pharmacological intervention BGP-15 demonstrated that after 10 days controlled mechanical ventilation the specific force of diaphragm muscle fibres increased by more than 100% compared to untreated muscle fibres. Furthermore when BGP-15 was administered to young and old rats, after 5 days controlled mechanical ventilation the age dependent significant drop in diaphragm fibre force production was restored, however only in the young. This concomitant increase in force in the young was observed also in the expression of heat shock protein 72. Thus, it is suggested that the increased Hsp72 expression, induced by BGP-15 is an indicator of the inhibition of the atrophy pathway (UPS) that as such attributes to an increased cross sectional area and specific force in only the young. It is of crucial importance to comprehend in more depth the effect of mechanical ventilation on limb and diaphragm function in the intensive care setting in order to ascertain any further age- related differences. We have determined here that BGP-15 is a possible intervention strategy that needs to be explored further to investigate the underlying mechanisms of action in order to implement the possible highly clinical significance of this research.