The role of heat shock proteins in glutamine-induced protection of skeletal muscle during sepsis

Lead Research Organisation: University of Liverpool
Department Name: Clinical Sciences

Abstract

The applicants are aware of the importance of public engagement in science. Dr McArdle was trained in media presentations as part of her Research into ageing-funded Fellowship and both applicants have participated in scientific interviews and discussions with local and national media and charity support groups.
Lay Summary:
Sepsis is the major cause of mortality in critically ill patients on the intensive care unit. Tissues of the critically ill patient in sepsis are exposed to a barrage of insults and this results in multiple organ failure. Despite detailed knowledge of multiple organ failure, treatment remains uncertain. Clinical experience suggests that the best hope for survival may be where circumstances allow the cells to withstand the attack and optimize their own defences. A patient with sepsis loses muscle at a staggering rate of 2-4 % per day. The ability to withstand sepsis appears to be particularly dependant upon available skeletal muscle. Over half of intensive care patients are over 65 years. The critical role of muscle mass in mortality during sepsis has profound implications for the elderly intensive care patient. The normal loss of skeletal muscle is such that a healthy individual aged 65 will have lost 30-40 %. The substantial rate of muscle loss during sepsis, taken together with this age-related loss is catastrophic and in the very least will prolong or inhibit subsequent recovery in the elderly and becomes a determinant of survival. We have identified a component of muscle, heat shock proteins (HSPs), which are crucial in maintaining muscle integrity in young and old individuals. The ability to produce HSPs fails in muscles of younger individuals during sepsis and the ability of muscles from even healthy elderly to produce HSPs in response to stresses is already severely compromised. A therapy which enhances the HSP content of muscle may provide significant benefit to both young and old individuals. Patients with sepsis have a marked deficiency of glutamine. Trials of patients fed glutamine during sepsis have shown that supplementation improves survival from multiple organ failure. However, the exact mechanism of glutamine action in these patients is unknown. Data from our laboratory and others suggests that glutamine may enhance HSP expression during stress and this is associated with protection of muscles. Understanding the role of HSPs in protecting against loss of muscle during sepsis and optimising the effects of glutamine is crucial to the development of a therapeutic rationale.

Technical Summary

Cells and tissues of the critically ill in sepsis are exposed to an inflammatory process that has profound consequences resulting in multiple organ failure and significant mortality. Modulation of the inflammatory pathway is a therapeutic approach which has received considerable attention. However, results from this have been disappointing. Therapies that enhance endogenous protection, salvage and repair mechanisms offer an exciting new strategy. The rate of loss of muscle in septic intensive care patients with multiple organ failure is between 2 and 4% per day. The ability to withstand sepsis appears to be dependant upon available skeletal muscle. Half of severely ill intensive care patients are over 65 years. The normal age-related loss of skeletal muscle between the years of 20 to 80 produces a 40% loss of muscle bulk. This substantial rate of muscle loss, taken together with the age-related loss of up to 40% of muscle bulk is catastrophic. Muscle cells of young individually are able to respond to stress by a rapid increase in protective proteins. We have demonstrated that one important component of this adaptation, heat shock proteins (HSPs) is crucial in maintaining muscle integrity. The ability to produce HSPs fails in muscles of younger individuals during sepsis and the ability of muscles from healthy elderly to produce HSPs in response to stresses is already severely compromised. Trials of patients fed glutamine during sepsis have shown that supplementation improves survival from multiple organ failure. However, the exact mechanism of glutamine action in these patients is unknown. Data from our laboratory and others suggests that glutamine may enhance HSP expression during stress and this is associated with protection of muscles. The aim of this study is to use transgenic technology to provide a comprehensive picture of the role of HSPs in preservation of muscle function in young and old mice during sepsis. This will be accompanied by a physiological approach to examine the ability of glutamine supplementation to enhance HSP content and preserve muscle function. The mouse model of LPS dosing will be used. This model is well established and has been commonly used as a model for sepsis. The study will use a combination of histochemical analysis of structure and physiological measurements. Understanding the role of HSPs in protecting against loss of muscle during sepsis and optimising the effects of glutamine is crucial to the development of a therapeutic rationale.

Publications

10 25 50
 
Description NICE guidelines (RDG)
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
Impact Professor Griffiths has implemented NICE guidelines related to ITU and parenteral nutrition/glutamine.
 
Description BBSRC DRINC
Amount £450,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 03/2011 
End 10/2014
 
Description The Dowager Countess Eleanor Peel Trust
Amount £150,000 (GBP)
Organisation The Dowager Countess Eleanor Peel Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2009 
End 12/2012
 
Title CFS cytokine database 
Description Cytokine protein array data from 90 CFS patients and 93 Healthy Control subjects/ 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? No  
Impact The work is currently being prepared for publication. The database comprises a large dataset of cytokine profiles from patients with Chronic Fatigue Syndrome and matched Healthy Control subjects which will be in a format searchable by others. 
 
Description Human muscle functional studies 
Organisation Liverpool John Moores University
Department Centre for Sport and Exercise Science
Country United Kingdom 
Sector Academic/University 
PI Contribution The expertise on HSP function in muscle and access to laboratories for analyses.
Collaborator Contribution The provision of functional testing staff and equipment to develop a means of examining the role of HSPs in modulating muscle function.
Impact 17488245 and this has led to a number of other publications not directly related to sepsis.
Start Year 2006
 
Description ME Association 
Organisation ME Association
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Provision of scientific expertise
Collaborator Contribution Patient cohort and access to group meetings etc.
Impact None
Start Year 2012
 
Description University of Leeds, cognitive fatigue 
Organisation University of Leeds
Department Institute of Psychological Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution My team provided the cell biology and patient cohort information to a collaborative study.
Collaborator Contribution The partners bring expertise in cognitive function and interventions.
Impact No outcomes so far. Collaboration is multi-disciplinary. Cell biology of muscle fatigue and central/cognitive aspects.
Start Year 2011
 
Description BBC news on-line 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Asked to comment on news reports. Although not directly related to outputs form this research, relevant in general terms.

Some contact from other organisations to advise regarding glutamine supplementation in ITU (RDG) or general muscle function and ageing (AMcA)
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
 
Description Engagement with ME/CFS paient groups and funders 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Scientific presentations to patients with CFS, targetted funders and carers.
Year(s) Of Engagement Activity 2014,2015,2016
 
Description Public Engagement at World Museum Liverpool 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact A large set of activities aimed at engagement of children with science, with focus on funded research areas within the Department/Institute.
Year(s) Of Engagement Activity 2014
 
Description School placements 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact School sixth form work experience in laboratories.

Led to a better understanding of the support or lack of support provided to inner-city schoolchildren with no background in higher education in their family.
Year(s) Of Engagement Activity 2012,2013,2014