David Maughan

Biography

Ph.D: Physiology and Biophysics, University of Washington, 1971. Postdoctoral fellowship: University of Bern, Switzerland, 1971-74. In 1974, Dr. Maughan joined the Molecular Physiology & Biophysics, University of Vermont. Visiting scholar: Columbia University (1981), Tohoku University Japan (1982, 1983), University of Heidelberg Germany (1984), University of York England (1991), Swiss Institute of Technology Switzerland (1992), University of Washington (2006

Research Interest

My primary focus is the molecular and cellular basis of striated muscle contraction. I have a related interest in the physical chemistry of the intracellular fluid in which muscle proteins are embedded. Through collaborations with other research laboratories my colleagues and I have employed a variety of genetic and bioengineering methods to probe muscle protein structure and function. These methods, many of which we have advanced in novel ways, include biomaterial analysis by means of small amplitude length perturbations and mass spectroscopy, time-resolved small-angle X-ray diffraction, and atomic force microscopy. Three experimental systems are used in our muscle studies: Drosophila melanogaster: Many of the genes and expressed proteins associated with fruit fly musculature are nearly the same as those in human muscle. Thus this small animal, which can be easily manipulated genetically, is an excellent model system to carry out integrated structural and functional analyses of proteins, particularly those involved in flight. For example, we identified regions of the motor myosin molecule that determine muscle speed by exchanging different regions of myosin from fast adult flight muscle and corresponding regions of myosin from slow embryonic muscle. We also found that substituting one amino acid for another in a regulatory subunit of myosin dramatically alters muscle power output and flight ability. By carrying out X-ray diffraction in living flies, we discovered that reduced recruitment of power-generating cross-bridges underlies the drop in power output. Through genetic engineering, we continue to investigate mutations (many potentially related to disease) in myosin and other proteins associated with the thick and thin filaments, as well as in enzymes involved in flight muscle metabolism. Our ultimate goal is to understand how these proteins interact and integrate into functional units. We are using new technologies or unusual combinations of existing technologies to propel research in this area. (see Figure 1 below) Our laboratory also carries out collaborative work using transgenic mouse models of human familial hypertrophic cardiomyopathy (FHC) and dilated cardiomyopathy. For example, one mouse line harbors the Arg403Gln missense mutation in the -myosin heavy chain, which causes one of the most lethal inherited diseases of the heart. Our studies reveal an altered affinity of myosin for actin and the substrate MgATP, such that cooperative activation of the thin filament, rate of force development, and oscillatory work output is promoted under some experimental conditions, but depressed under others. The direct but variable effect of the mutation (facilitating or debilitating, depending on isoform and ambient osmotic and ionic conditions), together with variable patterns of fibrosis and myofibrillar disorder that are secondary to the mutation, likely contribute to the diversity of clinical symptoms observed in FHC. (See Figure 2 below) Since 1998 we have applied techniques and knowledge gained from transgenic fly and mouse animal studies to human cardiac and skeletal muscle. Our goal is to understand the molecular basis of clinically and epidemiologically important diseases, with the ultimate aim of designing methods of diagnoses and treatment. Diabetic cardiomyopathy is one example. With our collaborating surgeons we have discovered specific, potentially deleterious alterations in dynamic stiffness in left ventricular biopsies from diabetic patients. As a group we are using the latest advances in immunohistochemistry, protein analysis, and biomechanical engineering to assess the contribution of connective tissue proliferation, isoform shifts and post-translational changes in myofibrillar proteins to disease-related alterations of human cardiac and skeletal muscle performance. (See Figure 3 below).