This is an application for competitive renewal of an R01 award entitled "Biophysical Basis of Muscle Functional MRI." In the previous cycle, we developed an improved understanding of the physiological basis of MRI contrast in skeletal muscle, especially blood oxygenation-level dependent (BOLD) effects, and developed diffusion-tensor MRI (DT-MRI) fiber tracking methods for quantitative characterization of muscle structure. In the proposed studies, we will advance these techniques further and then bring them to bear on Becker and Duchenne muscular dystrophy. These are severe neuromuscular disorders characterized by a missing or dysfunctional form of the cytoskeletal protein dystrophin. The resulting phenotype includes inflammation, muscle fiber necrosis with fat replacement and fibrosis, perfusion deficits, and reduced maximum stress- generating capability. In this application, we propose the novel hypothesis that fat replacement alters the normal muscle fiber architecture, impairing the normal relationships among muscle fiber geometry, stress and strain development, and perfusion. Therefore, our overall objective for this application is to advance MRI techniques for characterizing skeletal muscle structure and function, in order to elucidate novel aspects of the linkage between the skeletal muscle structural abnormalities and impaired mechanical and physiological performance in the dystrophinopathies.
Aim 1 is to quantify muscle architecture patterns in fat-infiltrated muscle and the normal relationship between architecture and strain development during isometric contractions. These studies will build on the advancements made in DT-MRI fiber tracking in the previous grant cycle and provide new understanding of normal muscle structure-function relationships.
Aim 2 is to develop and implement improved MRI methods for quantifying muscle blood flow, volume, and oxygenation changes during exercise and determine the effect of fiber curvature on perfusion.
This aim will capitalize on the improved understanding of BOLD contrast in skeletal muscle that we built during the last funding period and integrate these methods with perfusion and blood volume measurements for a comprehensive characterization of oxygen delivery and use by exercising muscle.
Aim 3 is to quantify the relationships among skeletal muscle architecture, muscle strain development, blood flow, and oxidative metabolism in healthy and dystrophic muscle. These studies will build on the work accomplished during the previous funding period, advance new tools for characterizing skeletal muscle in health and disease, and provide new insight into the pathological processes accompanying the loss of functional dystrophin in skeletal muscle.

Public Health Relevance

Becker muscular dystrophy is a severe neuromuscular disorder characterized by muscle wasting. However, the functional deficits associated with this wasting are not completely understood. In this application, we will develop new magnetic resonance imaging techniques for studying these deficits.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR050101-08
Application #
8243642
Study Section
Special Emphasis Panel (ZRG1-MEDI-S (09))
Program Officer
Boyce, Amanda T
Project Start
2003-07-31
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
8
Fiscal Year
2012
Total Cost
$336,960
Indirect Cost
$120,960
Name
Vanderbilt University Medical Center
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Skinner, Jack T; Robison, Ryan K; Elder, Christopher P et al. (2014) Evaluation of a multiple spin- and gradient-echo (SAGE) EPI acquisition with SENSE acceleration: applications for perfusion imaging in and outside the brain. Magn Reson Imaging 32:1171-80
Damon, Bruce M; Heemskerk, Anneriet M; Ding, Zhaohua (2012) Polynomial fitting of DT-MRI fiber tracts allows accurate estimation of muscle architectural parameters. Magn Reson Imaging 30:589-600
Englund, Erin K; Elder, Christopher P; Xu, Qing et al. (2011) Combined diffusion and strain tensor MRI reveals a heterogeneous, planar pattern of strain development during isometric muscle contraction. Am J Physiol Regul Integr Comp Physiol 300:R1079-90
Elder, Christopher P; Cook, Ryan N; Wilkens, Kenneth L et al. (2011) A method for detecting the temporal sequence of muscle activation during cycling using MRI. J Appl Physiol (1985) 110:826-33
Heemskerk, Anneriet M; Sinha, Tuhin K; Wilson, Kevin J et al. (2010) Repeatability of DTI-based skeletal muscle fiber tracking. NMR Biomed 23:294-303
Sanchez, Otto A; Copenhaver, Elizabeth A; Elder, Christopher P et al. (2010) Absence of a significant extravascular contribution to the skeletal muscle BOLD effect at 3 T. Magn Reson Med 64:527-35
Kan, J Herman; Heemskerk, Anneriet M; Ding, Zhaohua et al. (2009) DTI-based muscle fiber tracking of the quadriceps mechanism in lateral patellar dislocation. J Magn Reson Imaging 29:663-70
Heemskerk, Anneriet M; Sinha, Tuhin K; Wilson, Kevin J et al. (2009) Quantitative assessment of DTI-based muscle fiber tracking and optimal tracking parameters. Magn Reson Med 61:467-72
Louie, Elizabeth A; Gochberg, Daniel F; Does, Mark D et al. (2009) Transverse relaxation and magnetization transfer in skeletal muscle: effect of pH. Magn Reson Med 61:560-9
Damon, Bruce M (2008) Effects of image noise in muscle diffusion tensor (DT)-MRI assessed using numerical simulations. Magn Reson Med 60:934-44

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