David Maughan, Ph.D.


David  Maughan, Ph.D.

Professor

Background

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).

Contact

Office:
HSRF 122
802-656-4041



Research Description

Current Collaborators:
Drs. Jim Vigoreaux, Bradley Palmer, Mark Miller, Bertrand Tanner, Michael Toth, Martin LeWinter, Peter VanBuren.

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).

Current Publications:

Miller MS, Callahan DM, Slauterbeck JR, Savage PD, Maughan DW, Ades PA, Beynnon BD, Toth MJ (2016) Sex-specific Molecular And Cellular Functional Adaptations To Resistance Training In Inactive Older Adults: 1448 Board #101 June 2, 8: 00 AM – 9: 30 AM. Med Sci Sports Exerc 48(5 Suppl 1): 388.

Callahan DM, Tourville TW, Miller MS, Hackett SB, Sharma H, Cruickshank NC, Slauterbeck JR, Savage PD, Ades PA, Maughan DW, Beynnon BD, Toth MJ (2015) Chronic disuse and skeletal muscle structure in older adults: sex-specific differences and relationships to contractile function. Am J Physiol Cell Physiol 308(11): C932-43.

Carlson BE, Vigoreaux JO, Maughan DW (2014) Diffusion coefficients of endogenous cytosolic proteins from rabbit skinned muscle fibers. Biophys J 106(4): 780-92.

Miller MS, Bedrin NG, Callahan DM, Previs MJ, Jennings ME 2nd, Ades PA, Maughan DW, Palmer BM, Toth MJ (2013) Age-related slowing of myosin actin cross-bridge kinetics is sex specific and predicts decrements in whole skeletal muscle performance in humans. J Appl Physiol (1985) 115(7): 1004-14.

Palmer BM, Schmitt JP, Seidman CE, Seidman JG, Wang Y, Bell SP, Lewinter MM, Maughan DW (2013) Elevated rates of force development and MgATP binding in F764L and S532P myosin mutations causing dilated cardiomyopathy. J Mol Cell Cardiol 57: 23-31.

Wang Y, Tanner BC, Lombardo AT, Tremble SM, Maughan DW, Vanburen P, Lewinter MM, Robbins J, Palmer BM (2013) Cardiac myosin isoforms exhibit differential rates of MgADP release and MgATP binding detected by myocardial viscoelasticity. J Mol Cell Cardiol 54: 1-8.

Donaldson C, Palmer BM, Zile M, Maughan DW, Ikonomidis JS, Granzier H, Meyer M, VanBuren P, LeWinter MM (2012) Myosin cross-bridge dynamics in patients with hypertension and concentric left ventricular remodeling. Circ Heart Fail 5(6): 803-11.

 

Faculty Highlighted Publications

Maughan DW, Godt RE. Equilibrium distribution of ions in a muscle fiber. Biophysical Journal. 1989 Oct; 56(4): 717-722.

Maughan DW, Vigoreaux JO. An integrated view of insect flight muscle: Genes, motor molecules, and motion. News Physiol Sci. 1999 Jun; 14: 87-92.

Swank DM, Knowles AF, Suggs JA, Sarsoza F, Lee A, Maughan DW, Berstein SI. The myosin converter domain modulates muscle performance. Nature Cell Biol. 2002 Apr; 4(4): 312-316.

Dickinson M, Farman G, Frye M, Bekyarova T, Gore D, Maughan D, Irving T. Molecular dynamics of cyclically contracting insect flight muscle in vivo. Nature. 2005 Jan 20; 433: 330-333.

Palmer BM, Georgakopoulos D, Jannsen PM, Wang Y, Alpert NR, Belardi DF, Harris SP, Moss RL, Burgon PG, Seidman CE, Seidman JG, Maughan DW, Kass DA. Role of cardiac myosin binding protein C in sustaining left ventricular systolic stiffening. Circ Res. 2004 May 14;94:1249-1255.

Maughan DW, Henkin JA, Vigoreaux JO. Concentrations of glycolytic enzymes and other cystolic proteins in the diffusible fraction of a vertebrate muscle proteome. Mol Cell Proteomics. 2005 Oct;4(10):1541-1549.

Fukagawa NK, Palmer BM, Barnes WD, Leavitt BJ, Ittleman FP, LeWinter MM, Maughan DW. Acto-myosin crossbridge kinetics in humans with coronary artery disease: influence of sex and diabetes mellitus. J Mol Cell Cardiol. 2005 Nov;39(5):743-753.

Swank DM, Vishnudas VK, Maughan DW. An exceptionally fast actomyosin reaction powers insect flight muscle. PNAS. 2006 Nov 14;103(46):17543-17547.

Palmer BM, Wang Y, Teekakirkul P, Hinson JT, Fatkin D, Strouse S, VanBuren P, Seidman CE, Seidman JG, Maughan DW. Myofilament mechanical performance is enhanced by R403Q myosin in mouse myocardium independent of sex. Am J Physiol Heart Circ Physiol. 2008 Apr;294(4):H1939-H1947.

Miller MS, Lekkas P, Braddock JM, Farman GP, Ballif BA, Irving TC, Maughan DW, Vigoreaux JO. Aging enhances indirect flight muscle fiber performance yet decreases flight ability in Drosophila. Biophys J. 2008 Sep;95(5):2391-2401.

All Maughan publications