MRC Enterprise Studentship - Non-invasive phenotyping of muscle function using multi-nuclear MR
- Ladislav Valkovic
LEAD SUPERVISOR: DR LADISLAV VALKOVIČ, RADCLIFFE DEPARTMENT OF MEDICINE
Co-supervisor: Prof Damian Tyler, Department of Physiology, Anatomy and Genetics
Commercial partner: RAPID Biomedical GmbH, Rimpar, Germany
Breathlessness, fatigue on exertion and exercise intolerance are common features of obesity, type II diabetes and heart failure. Although central (cardiac) metabolic impairment typifies these conditions, peripheral (muscle) metabolic impairment is simultaneously occurring, and its contribution to exercise intolerance is poorly understood. Whilst it seems obvious that skeletal muscle would be a target for therapeutic intervention to improve exercise capacity, there are currently no muscle targeted therapies. As such, improved assessment of skeletal muscle metabolism in these conditions, is an exciting and important target.
Magnetic Resonance Spectroscopy (MRS) is a non-invasive technique capable of assessing tissue chemical composition and metabolic processes in vivo. In particular, proton (1H)-MR provides insight into lipid metabolism and pH buffering through intramyocellular lipids, acetyl-carnitine and carnosine content quantification, respectively. In addition, tissue oxygenation and perfusion can be assessed using 1H-MR. Mitochondrial metabolism can then be probed using phosphorus (31P)-MRS through the acquisition of phosphocreatine dynamics during and after exercise. In a complementary manner, carbon (13C)-MRS provides insight into glucose metabolism and glycogen production and storage in muscle. Hence, only a combination of 1H-, 31P- and 13C- MRS in one multi-nuclear protocol could provide a comprehensive assessment of the muscle metabolism phenotype.
To effectively combine all three nuclei into one protocol, a novel dedicated triple tuned radio-frequency (RF) coil capable of excitation and acquisition of MR signal at three different frequencies needs to be designed. This constitutes a significant challenge since adding the electronics needed for additional nuclei causes a drop in performance of the coil. Novel efficient decoupling techniques will need to be designed and tested, e.g., using different coil geometries for the different nuclei.
The objectives of this collaborative project are:
1) To design and construct an efficient triple tuned RF coil for comprehensive muscle metabolism assessment.
2) To phenotype skeletal muscle metabolism in a group of heart failure patients
This will include the design of efficient decoupling (supported by the market leader in design and construction of non-proton RF coils, i.e. Rapid Biomedical GmbH), simulations of magnetic fields around the new RF coil designs, construction and testing of the new hardware for performance and safety. The final coil design will be optimised for the planned interventional study. The examination protocol would include: i) measurement of intramyocellular lipids, acetyl-carnitine, creatine and carnosine by 1H-MRS, pre and post exercise; ii) interleaved acquisition of 31P and 13C MRS during exercise for assessment of metabolic fluxes and glycogenolysis rates; and iii) interleaved 31P and 1H MR during recovery for mitochondrial metabolism and tissue perfusion assessment. The combination of these metabolic measures will provide an unparalleled insight into muscle metabolism in vivo and will allow identification of an individualized muscle metabolism phenotype. This will be applied in an interventional study of obese heart failure patients enrolled to our successful very low energy diet programme.
The ability to non-invasively define a muscle metabolism phenotype, in parallel to cardiac metabolism assessment, will ultimately allow us to design muscle targeting therapies for heart failure patients.
Funding for successful applicants to this project is provided by the MRC Enterprise Studentship Programme. Further information about the MRC Enterprise studentships can be found on the Medical Sciences Division website.