Greater understanding of the aetiology of skeletal muscle atrophy and loss of muscle function during periods of unloading is important for injury management of athletes. The aim of this project is to quantify changes in global gene expression of human skeletal muscle in response to 14 days of immobilisation.
Fifty healthy young men will have a leg placed in a full-length cast for 14 days. Quadriceps mass will be quantified before and after the 14 day intervention using magnetic resonance imaging to determine muscle atrophy, and pre- and post-intervention muscle biopsy samples will be collected for subsequent RNA-sequencing of changes in inducible gene expression in response to short-term muscle unloading. These data will provide new information on early transcriptional reprogramming with muscle disuse in human skeletal muscle
Characterising the molecular profile of muscle wasting when physically active individuals undertake an enforced period of complete immobilisation will provide new information on the genetic bases of skeletal muscle atrophy.
The primary aim of the proposed study is to determine changes in inducible gene expression in the early (3 d) and short-term (14 d) immobilisation period. The research question is novel and will have the capacity to inform sports medicine and exercise science in characterising individuals ‘at-risk’ of rapid degeneration of muscle mass with disuse or those that may be “protected” from muscle loss with short-term unloading. The use of the RNA-sequencing analysis will provide superior data than any previous studies examining genetic profiles associated with disuse atrophy.
- Associate Professor Vernon Coffey, Bond University
- Associate Professor Kevin Ashton Bond University
- Professor Nuala Byrne, Bond University
Skeletal muscle is a highly adaptable tissue but its capacity to maintain protein balance and regenerate/repair diminishes with physical inactivity, chronic disease and aging which impair mobility and function.
Our study will use a unique animal model of different genetic backgrounds and divergent adaptive capacity to gain new information on mechanisms regulating skeletal muscle mass. We will compare the muscle response to overload, disuse atrophy and repair after injury in selectively-bred rats with contrasting muscle metabolism and exercise capacity. This study will identify mechanisms and specific targets that protect skeletal muscle mass and promote growth/regeneration to counteract muscle wasting.
The findings from this study extend across sports science and clinical research applications, and will also have implications for repair and regeneration from injury.
Failure to attain and maintain peak muscle mass predisposes an individual to greater risk of disability and loss of functional capacity with aging, injury or disease. Moreover, the accelerated muscle wasting in many chronic diseases has debilitating health consequences additive to the primary disease pathology. It is imperative to develop and implement effective therapeutic strategies to combat muscle loss, particularly if the goal is to close the gap between life expectancy and healthy, functional life expectancy. While knowledge gained from transgenic models is important to identify therapeutic targets, translational studies in appropriate biological model systems are essential to determine the efficacy and/or validity of their potential. The proposed study will be the first to use an innovative inbred strain of rodents artificially selected for exercise training responses to determine adaptive/maladaptive responses that modulate skeletal muscle mass.
We would like to look across the lifespan at healthy people with risk factors for chronic disease, people with early stage chronic disease and people with longstanding chronic disease. We have three basic study designs we would propose, within which we will address the hypotheses linking genetic profile and phenotypic adaptation to exercise, as noted below:
- Conduct cross-sectional analyses across the lifespan to specify the genetic profiles that explain a portion of the variance in the following five domains relevant to chronic disease:
- Body Composition & Nutritional status
- Exercise Capacity and Performance
- Cardiovascular and Metabolic Risk Profile
- Neurological & Psychological Function
- Musculoskeletal Morphology and Metabolism
- Determine genetic profiles that predict the severity or presentation of specific chronic diseases which have been linked to lifestyle (particularly cardiometabolic and musculoskeletal disease), as well as genetic profiles that predict robust changes and adaptations related to lifestyle interventions across the above five themes.
- Measure change in epigenetic profile, mRNA and protein expression to assess if epigenetic regulation of gene expression changes over time due to lifestyle interventions and whether these changes predict a portion of the adaptation to lifestyle modification.
This study will be led by Professor Maria Fiatarone Singh at University of Sydney, with input from all partners in the CRN.
Aim of the study
The aim of this research study is to identify genetic polymorphisms that contribute to increased risk of, or protection from tendon and bone injuries sustained through participation in physical activity. This knowledge will be used to develop programs for the prevention of injury in sport and physical activity.
Participation in physical activity has been shown to be extremely beneficial to health however; participation in both recreational and competitive sports increases the risk of acquiring injuries of both the soft tissues and bones. The cost of sports injuries in Australia was estimated at $1.65 billion a year (Orchard & Finch, 2002). At the elite level, the occurrence of these exercise-induced injuries are common and can prevent athletes from both training and competing, limiting the progress of some athletes to top level competition (Palmer-Green, 2103). Sporting success at the international level is significantly impacted by loss of training and competition time through injury. Research that examines new approaches to reducing the number of days lost to training through injury or illness and research that examines mechanisms that have the potential to change injury or illness management are a priority for the Australian elite sport sector. Identification of factors predisposing athletes to injury will allow coaches to customise training loads for individuals, according to injury susceptibility. Clinicians will be able to administer preventative, evidence-based interventions to reduce the rate of athlete injury.
This research study will focus on the role of genetics in exercise-induced injuries. Understanding genetic risk of or protection from exercise-induced injuries of the tendon and bone will allow coaches, trainers, physicians and physical therapists to develop training programs that account for such conditions. This study aims to identify genetic polymorphisms (genetic variation resulting in different biochemical characteristics) that contribute to increased risk of, or protection from tendon and bone injuries sustained through participation in physical activity. The proposed study will provide world-first evidence regarding the association between genetic polymorphisms and susceptibility to exercise-induced bony stress injuries.
With advancements in molecular biology, the use of personalised medicine to prevent and treat exercise-related medical conditions will become a reality. Understanding genetic risk of or protection from exercise-induced injuries of the tendon and bone will allow coaches, trainers, physicians and physical therapists to develop training programs that account for such conditions. In addition, identification of genetic polymorphisms in relation to bone and tendon health may give rise to further research into potential causes, therapies, personalised training strategies and diagnostic tools in the field of bone and tendon injuries.
Low cardiorespiratory fitness (e.g. aerobic power (VO2peak)) is highly associated with cardiovascular disease, diabetes and mortality from all causes. To alleviate the health burden associated with low fitness, exercise training guidelines recommend that people undertake physical activity to improve VO2peak. However, it is well known that there is a large inter-individual variability in improvements in VO2peak in response to exercise training. Given that high levels of cardiorespiratory fitness are one of the best predictors of the risk of morbidity and mortality it is important to understand what factors (e.g. genetic) predict the variability in the exercise training response.
The aim of this study is to identify genetic variants explaining the change in VO2peak that occurs in response to high intensity interval training (HIIT). Data from previous tightly-controlled studies using HIIT from Norway, Canada and Australia will be used. Participants with measured VO2peak data who achieved high compliance with supervised HIIT training (>90%) will be asked to provide saliva for genetic analysis (~n=1000). Additional demographic and clinical data from the studies will also be collated. Genetic variants identified in a previous study (Heritage Study) will be examined
- Professor Jeff Coombes, University of Queensland
- Professor Ulrik Wisloff, Norwegian University of Science and Technology
- Dr Jonathon Little, University of British Columbia
- Professor Nuala Byrne, Bond University
One of the key outcomes of the CRN is to establish a biobank of biological samples from participants store blood, saliva, tissue, and DNA/RNA samples with the input of CRN collaborative partner institutions, and facilitate access for genetic analyses. A biobank is a long term, renewable source of bio-specimens that are collected in connection with clinical trials or public health surveys. Typically such a resource is used to catalogue bio-specimens and provide long term access to samples to multiple researchers for multiple purposes such as genomic research studies. While biobanks have invoked multiple debates, strict regulations are put in place to ensure storage integrity and purity of every specimen.
Samples are collected in connection with clinical trials or public health surveys across the CRN collaborative research projects. A process of informed consent for the biobank is in place, including a clear outline of the facts, implications, and future consequences of submitting biological samples to the biobank. Participants are able to consent to be part of a collaborator project only, with consent to have their sample biobanked for future projects as a separate opt-in part of each consent form.
The infrastructure of the biobank has been set up inside a PC2 certified facility requiring restricted swipe access, at Bond University Health Science and Medicine faculty laboratories. A dedicated CRN freezer bank comprising two -80 degree C freezers with CO2 backup and one -30 degree C freezer, all with necessary alarms to ensure maintenance of UPS, has been established to store samples long-term. A dedicated LIMS computing system capable of handling data and data protection is necessary for any stable biobank. The platform used in the CRN biobank is the Finland-based BC (Biocomputing) system. This system detains a large panel of data management features with the LIMS module being called BC sample, while also allowing incorporation of genomic data with the LIMS module BC SNP. The BC system is able to log new users, grant permissions to certain datasets to different user sets to restrict data access, place restriction on exports, and data back-up functionalities, through a secure web access encrypted connection. This system also provides ongoing remote maintenance and support of the database, access to BC Technical Support for troubleshooting and training, and automatic updates.
A sample receipt system has been implemented in which specimens arriving at the biobank or collected at Bond for the biobank are labelled with unique barcode identifiers utilising a thermal transfer printer and superior cold-resistant nylon label media, ensuring that samples can be tracked easily within the lab, avoiding duplication of identifiers within the biobank, and guaranteeing that sample labels will be legible and stable in long-term -80 degree C storage. Use of a barcode and CRN specimen ID code also allows sample de-identification which protects the privacy of study participants. No identity will be revealed of any participant through research reporting and proper confidentiality of the subject will be totally protected as only aggregate data will be used to disseminate research results. However, within the LIMS system, identifiable information is retained in a separate restricted database with limited staff access, in order to fulfil three functions: in order to be able to withdraw any participant from the biobank or study who may request withdrawal; in order to request participants for additional sampling should initial samples fail experimentation quality controls; and in order to release information back to participants if any identified reportable risk factors are discovered (as per the ethically defensible plan).
The ability to obtain specific collections of samples required for individual research, preserved in the right conditions with the integrity and purity of sample maintained at a high standard for research, is increasingly essential for scientific researchers worldwide. Setting up a biobank as a resource across CRN collaborative research institutes has enhanced and complemented our research and helped keep ahead of the aims of the CRN. The overall aim of the CRN is to improve our understanding of the relationship between genes, physical activity and health status. Studies have been developed across collaborative research institutions to achieve this aim. The combination of these studies through the pooling of data and samples from overlapping cohorts via the CRN biobank will provide a better understanding of the genetic contribution to chronic disease, exercise-induced injury and a high ability to adapt to intense exercise. Overall this ability to source these overlapping sample pools from a biobank will be crucial to providing information about the clinical and genetic/biological processes involved with these groups of participants and help provide greater insight into the role of genetics in exercise and health.
The CRN-AESS Research Methods Library (RML): building research capacity at Bond
The CRN-AESS takes a deliberately ‘Bond-centric’ approach, with the over-arching aim “to build research capacity and improve the supporting administrative framework to increase research productivity, quality and impact in the fields of health, exercise, and sport science at Bond University and across the network” (CRN Operational Plan). The key challenge for the CRN-AESS is how to harness the collective experience, knowledge, and skills from established, research-intensive partner organisations to ensure that gains in research capacity at Bond ‘live beyond’ the 2013-2017 funding period.
One step towards achieving this is putting mechanisms in place to formalise knowledge transfer from the partner institutions to Bond. The CRN-AESS Research Methods Library (RML) is a digital repository designed to capture the research protocols used across the diverse range of CRN-AESS-funded seeding grants and cross-institutional research projects in clinical research, exercise and sport science, and injury management and human performance.
Design and implementation of the CRN-AESS RML
The CRN-AESS RML will embrace the principles of open science, providing a dynamic, open access collection of research protocols. It will be hosted in Bond’s digital repository, and will be discoverable via direct access, and links from Google, Google Scholar, Bond Library’s Alma and Primo systems, and the Research Data Australia site.
The RML will be enhanced by persistent identifiers (DOIs), geolocation maps, links to publications and institutions, and a commentary feature for each record to provide a feedback mechanism for discussion to foster discussion about research methodology. It is anticipated that data visualisation, for example video capture, will also be incorporated as an additional enhancement of the methods collection. An ‘Expert Gallery’, featuring CRN-AESS researchers, may also be incorporated into the RML community site. External collaborations will also be featured including interactions with other national and international research groups and exercise and sport organisations.
It is anticipated that the RML will provide the following tangible benefits to Bond, other CRN- AESS partners, and the broader scientific community:
1. Meeting strategic targets and creating an enduring legacy of CRN-AESS funding.
The RML directly addresses key strategic foci as outlined in the CRN-AESS Implementation Plan. This centralised methods repository will formalise knowledge transfer from CRN partner institutions to Bond, ensuring that knowledge and skills developed during the collaborative research process are available to both current and future researchers.
2. Showcasing the breadth of CRN-funded projects, and fostering links with the broader exercise science research community.
The open accessibility of the collection, together with the open comments feature that will be incorporated into the digital record of each Method, will facilitate engagement with the RML, and help to nurture future research collaborations.
3. Encouraging a culture of continuous improvement.
The collection will be designed to endure and grow with enhancements that will complement the discoverability and accessibility of the data with an open communication channel for global feedback, and possible improvement of the research methodologies.
4. Increasing transparency and accountability.
Openly accessible, detailed research protocols facilitate critical evaluation of research by reviewers, granting bodies, scientists, clinicians, and others who engage with the research.
5. Facilitating study replication.
‘Irreproducibility’ is a major issue across many areas of science. Inability to access detailed research protocols/methods used in the original research is one factor that impedes efforts to replicate a study . Methods sections in published papers often lack the detail necessary to reproduce the study . For example, 40-89% of biomedical randomised controlled trials do not contain sufficient methodological information to enable replication . This does not necessarily mean that robust protocols were not used, just that they may not have been completely reported. Open access repositories such as the RML provide a mechanism for reporting research methods.
6. Reducing redundancy.
Weeks, and often months, are invested in developing methods, some of which may already be well-specified in another lab. Openly accessible methods can shift the focus from developing methods to instead modifying and applying these methods to address important questions. This is especially pertinent for higher degree research (HDR) students and early career researchers (ECRs), who often have very limited time (and funding) to produce high quality research outcomes.