Research Core C: Animal Repository and Measurement of Muscle Force, David D. Thomas, PhD The purpose of this core is to provide an animal repository, focused on mouse models of muscle disease, and to provide facilities and expertise for the measurement of muscle force at all levels from living animals to single molecules. The primary function of muscle is force generation. To further characterize the pathophysiology of muscle disease and establish accurate methods for determining the time course of disease progression and response to treatment, we will characterize force and molecular structure in experimental subjects, including animal models that will be available and affordable to all MD Center researchers. These facilities will provide important resources for virtually all projects of the MD center, and will comprise a testing facility and methodology valuable to all muscle investigators.
Specific aims are to establish facilities for the following:
Aim 1 : Maintain breeding pairs of selected mouse models of muscular dystrophy and other myopathies, so MD Center investigators can more effectively perform collaborative studies of the different models.
Aim 2 : Measure stimulated muscle force in vivo in humans, mice, and other animals, directly activating the innervating nerve to obviate central nervous system and systemic effects.
Aim 3 : Measure force of intact muscle in vitro from whole mouse muscles and bundles of fibers from human biopsies by electrical or chemical stimuli, to measure twitch and tetanic force, and rates of relaxation and activation.
Aim 4 : Measure force of skinned fibers in vitro, to assess myofilaments separately from electrochemical function.
Aim 5 : Measure force at the molecular level, using either (a) specrroscopic probes that reveal molecular structural and dynamic states that correspond to force generation or mechanical strength, and (b) laser tweezers (laser traps), which measures directly the mechanical properties of single molecules. Most of these mouse models and technical capabilities are currently operational at the University of Minnesota, but due to technical complexity and separate funding mechanisms, each mouse model and technique is currently accessible at a practical level for a limited number of investigators, and expenses currently limit the extent to which these animals and techniques are combined in collaborative projects. Through a centrally organized and funded Core, we will make them accessible and affordable to all MD Center investigators, greatly increasing the coherence and effectiveness of MD Center research.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Center Core Grants (P30)
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Special Emphasis Panel (ZAR1-CHW-G)
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University of Minnesota Twin Cities
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McCaffrey, Jesse E; James, Zachary M; Thomas, David D (2015) Optimization of bicelle lipid composition and temperature for EPR spectroscopy of aligned membranes. J Magn Reson 250:71-5
Belanto, Joseph J; Mader, Tara L; Eckhoff, Michael D et al. (2014) Microtubule binding distinguishes dystrophin from utrophin. Proc Natl Acad Sci U S A 111:5723-8
Dong, Xiaoqiong; Thomas, David D (2014) Time-resolved FRET reveals the structural mechanism of SERCA-PLB regulation. Biochem Biophys Res Commun 449:196-201
Gruber, Simon J; Cornea, Razvan L; Li, Ji et al. (2014) Discovery of enzyme modulators via high-throughput time-resolved FRET in living cells. J Biomol Screen 19:215-22
Moen, Rebecca J; Klein, Jennifer C; Thomas, David D (2014) Electron paramagnetic resonance resolves effects of oxidative stress on muscle proteins. Exerc Sport Sci Rev 42:30-6
Mourkioti, Foteini; Kustan, Jackie; Kraft, Peggy et al. (2013) Role of telomere dysfunction in cardiac failure in Duchenne muscular dystrophy. Nat Cell Biol 15:895-904
Goc, Anna; Al-Azayzih, Ahmad; Abdalla, Maha et al. (2013) P21 activated kinase-1 (Pak1) promotes prostate tumor growth and microinvasion via inhibition of transforming growth factor ýý expression and enhanced matrix metalloproteinase 9 secretion. J Biol Chem 288:3025-35
Muretta, Joseph M; Petersen, Karl J; Thomas, David D (2013) Direct real-time detection of the actin-activated power stroke within the myosin catalytic domain. Proc Natl Acad Sci U S A 110:7211-6
Moen, Rebecca J; Thomas, David D; Klein, Jennifer C (2013) Conformationally trapping the actin-binding cleft of myosin with a bifunctional spin label. J Biol Chem 288:3016-24
Arpke, Robert W; Darabi, Radbod; Mader, Tara L et al. (2013) A new immuno-, dystrophin-deficient model, the NSG-mdx(4Cv) mouse, provides evidence for functional improvement following allogeneic satellite cell transplantation. Stem Cells 31:1611-20

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