POSTDOCTORAL TRAINING

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1 2 Curriculum Vitae JULIAN E. STELZER, PhD CONTACT DETAILS Phone: EDUCATION McGill University, Montréal, Canada BS, Physiology University of Saskatchewan, Saskatoon, Canada MS, Kinesiology Oregon State University, Corvallis, Oregon PhD, Muscle Physiology, Exercise and Sport Science. PhD Thesis: Protein isoform-function relationships of single skeletal muscle fibers from weight-bearing and hindlimb suspended mice Supervisor: Dr. Jeffrey J. Widrick POSTDOCTORAL TRAINING 2002-Present Research Associate/Postdoctoral Fellow, Department of Physiology, University of Wisconsin, Madison Mentor: Dr. Richard L. Moss. FUNDING Completed AHA Z American Heart Association Greater Midwest Affiliate (Postdoctoral Fellowship) Functional effects of familial hypertrophic cardiomyopathy mutations in troponin-t Role: Principal Investigator ($88,000). Pending American Heart Association National Center (Scientist Development Grant) Regional distribution of contractile proteins in healthy and failing human myocardium. Role: Principal Investigator ($260,000). REFEREEING American Journal of Physiology Aviation Space and Environmental Medicine Biophysical Journal Circulation Research

2 3 International Journal of Sports Medicine Journal of Applied Physiology Journal of Gerontology Journal of Physiology Physiological Genomics PROFESSIONAL MEMBERSHIPS American Heart Association American Physiological Society American College of Sports Medicine Biophysical Society TEACHING EXPERIENCE EXSS 436/536 Advanced Cardiovascular Dynamics EXSS 474/574 Advanced Exercise Physiology Lab Methods EXSS 131 Introduction to Exercise and Sport Science PUBLICATIONS Published Peer Reviewed Journal Articles Stelzer JE, Patel JR, Walker JW, Moss RL. (2007). Respective roles of cmybp-c and ctni in the myofibrillar force response to PKA phosphorylation. Circ Res. 101: Stelzer JE, Brickson SL, Locher MR, Moss RL. (2007). Role of myosin heavy chain composition in the stretch activation response of rat myocardium. J Physiol. 579: Stelzer JE, Patel JR, Moss RL. (2006). PKA-mediated acceleration of the stretch activation response in murine skinned myocardium is eliminated by ablation of cmybp -C. Circ Res. 99: Includes Editorial by Granzier HL, Campbell KB, New insights in the role of cardiac myosin binding protein-c as a regulator of cardiac contractility. Circ Res. 99: Stelzer JE, Moss RL. (2006). Contributions of stretch activation to length -dependent contraction in murine myocardium. J Gen Physiol. 128: Stelzer JE, Patel JR, Moss RL. (2006). Acceleration of stretch activation in murine myocardium due to phosphorylation of myosin regulatory light chain. J Gen Physiol. 128: Stelzer JE, Dunning SB, Moss RL. (2006). Ablation of cardiac myosin-binding protein-c accelerates stretch activation in murine skinned myocardium. Circ Res. 98: Includes Editorial by Epstein ND, Davis JS, When is a fly in the ointment a solution and not a problem? Circ Res. 98: Stelzer JE, Fitzsimons DP, Moss RL. (2006). Ablation of myosin binding protein-c accelerates force development in mouse myocardium. Biophys J 90:

3 4 Stelzer JE, Larsson L, Fitzsimons DP, Moss RL. (2006). Activation dependence of stretch activation in mouse skinned myocardium: implications for ventricular function. J Gen Physiol. 127: Includes Commentary by Campbell KB, Chandra M, Functions of stretch activation in heart muscle. J Gen Physiol. 127: Stelzer JE, Patel JR, Olsson MC, Fitzsimons DP, Leinwand LA, Moss RL. (2004). Expression of cardiac troponin T with COOH-terminal truncation accelerates cross-bridge interaction kinetics in mouse myocardium. Am J Physiol Heart Circ Physiol. 283:H1756-H1761. Stelzer JE, Widrick JJ. (2003). Effect of hindlimb suspension on the functional properties of slow and fast soleus fibers from three strains of mice. J Appl Physiol. 95: Shoepe TC, Stelzer JE, Garner DP, Widrick JJ. (2003). Functional adaptability of muscle fibers to long-term resistance exercise. Med Sci Sport Exerc. 35: Widrick JJ, Maddalozzo GF, Lewis D, Valentine BA, Garner DP, Stelzer JE, Shoepe TC, Snow CM. (2003). Morphological and functional characteristics of skeletal muscle fibers from hormone-replaced and nonreplaced postmenopausal women. J Geront A Biol Sci Med Sci. 58:3-10. Widrick JJ, Stelzer JE, Shoepe TC, Garner DP. (2002). Functional properties of human muscle fibers after short-term resistance exercise training. Am J Physiol - Reg Int Comp Physiol. 283:R408-R416. Peer Reviewed Journal Articles Submitted or in Preparation Stelzer JE, Chen PP, Patel JR, Norman HSN, Moss RL. Transmural differences in myosin heavy chain isoform expression modulates the timing of myocardial force generation in porcine left ventricle. Submitted to Circulation. Tong CW, Stelzer JE, Greaser ML, Powers PA, Moss RL. Phosphorylation of myosin binding protein-c affects myofilaments mechanics. Submitted to Circ Res. Fitzsimons DP, Stelzer JE, Jin JP, Moss RL. Expression of fast skeletal muscle troponin T in cardiac muscle alters the rate of cooperative cross-bridges recruitment during force development. Submitted to J Biol Chem. Locher MR, Razumova MV, Stelzer JE, Norman HSN, Patel JR, Moss RL. Impact of myosin heavy chain expression on the fundamental rate constants of cross-bridge attachment and detachment in rat myocardium. Submitted to Circ Res. Stelzer JE, Norman HSN, Patel JR, Moss RL. Regional differences in mechanical properties of porcine skinned myocardium: Implications for whole heart function. In preparation. Stelzer JE, Fitzsimons DP, Moss RL. Cardiac myosin binding protein-c: Regulation of cardiac contractility in health and disease. In preparation.

4 5 Published Abstracts Stelzer JE, Chen PP, Norman HS, Patel JR, Moss RL (2008). Transmural Differences in Myosin Heavy Chain Isoform Expression Modulates the Timing of Myocardial Force Generation in Porcine Left Ventricle. Biophys J. 94:A299. Tong C, Stelzer JE, Greaser ML, Powers PP, Moss RL (2007). Absence of protein kinase A phosphorylation of cardiac myosin binding protein causes myocardial dysfunction and hypertrophy. Circulation. 116:S142. Stelzer JE, Patel JR, Walker JW, Moss RL. (2007). PKA phosphorylation of cmybp-c accelerates the myocardial stretch activation response. Biophys J. 92:A419. Locher MR, Razumova MV, Stelzer JE, Moss RL. (2007). Importance of myosin heavy chain expression as a determinant of contraction kinetics in pig myocardium. J Mol Cell Cardiol. 42:871. Locher MR, Razumova MV, Stelzer JE, Norman HSN, Patel JR, Moss RL. (2007). Impact of myosin heavy chain expression on the fundamental rate constants of cross-bridge attachment and detachment in rat myocardium. Biophys J. 92:A414. Stelzer JE, Moss RL. (2006). Sarcomere length dependent modulation of stretch activation in myocardium. J Mol Cell Cardiol. 40:902. Stelzer JE, Patel JR, Fitzsimons DP, Moss RL. (2006). Effects of protein kinase A phosphorylation on stretch activation kinetics of wild-type and myosin binding protein-c null mouse myocardium. Biophys J. 90:B411. Stelzer JE, Patel JR, Fitzsimons DP, Moss RL. (2005). Effects of cmybp-c ablation on crossbridge kinetics and stretch activation in mouse myocardium. Biophys J. 88:B437. Patel JR, Fitzsimons DP, Stelzer JE, Walker JW, Moss RL. (2005). Effect of myosin regulatory light chain phosphorylation on mechanical properties of murine myocardium vary with temperature. Biophys J. 88:B436. Patel JR, Fitzsimons DP, Stelzer JE, Wang H, Moss RL, Walker JW. (2005). Phosphorylation of myosin light chain increases Ca 2+ sensitivity and cross-bridge cycling kinetics in murine myocardium expressing non-phosphorylatable cardiac troponin I. Biophys J. 88:B435. Stelzer JE, Patel JR, Fitzsimons DP, Walker JW, Moss RL (2004). Length dependence of activation in mice expressing troponin I with non-phosphorylatable PKA sites. J Mol Cell Cardiol. 36:388. Stelzer JE, Patel JR, Olsson CM, Fitzsimons DP, Leinwand LA, Moss RL (2004). Altered thin filament cooperativity and cross-bridge kinetics due to expression of truncated cardiac troponin T. Biophys J. 86:P1799.

5 6 Stelzer JE, Widrick JJ (2002). Effects of 7 days of hindlimb suspension on contractile function of soleus single muscle fibers from C57BL/6 mice. FASEB J. 16:A105. Shoepe TC, Stelzer JE, Garner DP, Widrick JJ (2002). Contractile function of single muscle fibers from chronically resistance-trained humans. FASEB J. 16:A343. Widrick JJ, Maddalozzo GF, Garner DP, Stelzer JE, Shoepe TC, Snow CM (2002). Estrogen replacement therapy and contractile function of muscle fibers from early postmenopausal women. FASEB J. 16:A17. Garner DP, Stelzer JE, Shoepe TC, Mull JJ, McCubbin J, Widrick JJ (2001). Cross-bridge mechanisms of muscle weakness in multiple sclerosis. FASEB J. 15:A814. PRESENTATIONS and INVITED TALKS (last 3 years) 1) University of Colorado, Department of Cardiology, Denver, CO, 09 / ) Boston Biomedical Research Institute, Boston, MA, 03/ ) Case Western Reserve University, Dept. of Cardiology, Cleveland, OH, 01/ ) Cornell University. Department of Cardiology, New York, NY, 01/ ) Northwestern University, Department of Cardiology, Evanston, Il, 11/ ) Biophysical Society National Meeting, Baltimore, MD, 03/2004. REFERENCES 1) Dr. Richard Moss. Professor and Chair, Department of Physiology, University of Wisconsin Medical School , rlmoss@physiology.wisc.edu 2) Dr. Kerry McDonald. Associate Professor, Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine , mcdonaldks@health.missouri.edu 3) Dr. Gail Robertson. Associate Professor, Department of Physiology, University of Wisconsin Medical School , robertson@physiology.wisc.edu

6 7 RESEARCH INTERESTS The long-range goal of my research is to understand the molecular mechanisms which govern the regulation of striated muscle contraction and the role of contractile proteins in cardiac myopathies and heart failure. The research program is focused on defining the modes of regulation at the myofilament level which alter cardiac function at the global level, with particular emphasis on identifying potential targets of therapeutic intervention in human patients with arrhythmia, ischemic heart disease, and hypertrophic cardiomyopathy. This aim will be accomplished by basic and translational studies which utilize knowledge gathered from investigations in animal models to solve clinical problems in human heart failure patients. Contributions of Contractile Proteins to Heterogeneous Mechanical Function in Healthy and Failing Myocardium Despite operating as a single contracting unit, the left ventricle shows extensive electrica l and mechanical heterogeneity, i.e. the pattern of ventricular activation and the timing and extent of muscle contraction and lengthening in the human heart varies on a regional basis. Thus, efficient cardiac function requires precise coordination of electrical activation and myocardial contraction, the importance of which is underscored by the observation that disruptions in the pattern of ventricular electro-mechanical activation have been implicated in the development of cardiac dysfunction, congestive heart failure, and arrhythmias. The exact mechanisms underlying the heterogeneity of mechanical function across the ventricular wall in human myocardium, however, remain unclear. To date, most studies have focused on the regional differences in the electrical properties of ventricular myocytes while relatively little is known about the regional diversity in mechanical properties. In recent studies of healthy porcine and human myocardium I found that the expression of contractile protein isoforms and the phosphorylation sta tus of these proteins vary across the ventricular wall in the left ventricle. These differences contributed significantly to the regional diversity in the mechanical properties of myocytes isolated from the endocardium and epicardium as well as with in vivo electrocardiography and strain measurements. These studies are the first to clearly show the functional relevance of regional contractile protein expression in porcine and human hearts, and show that changes in regional mechanical contractility contribute to altered global cardiac function in failing hearts in part, due to disruptions in the sequence and timing of regional force generation across the ventricular wall which impairs systolic function. In follow-up studies I investigated how the disease process affects the regional pattern of contractile protein expression and phosphorylation in the left ventricle during acute ischemia bouts in porcine hearts and in myocardial samples isolated from chronic heart failure patients. Preliminary data show that cardiac ischemia and chronic heart failure results in a significant redistribution of the pattern of contractile protein expression and phosphorylation status, and these changes are well correlated with impaired mechanical function in vivo. Future studies will continue to investigate the correlation between regional mechanical function and contractile protein expression and phosphorylation status in normal, hypertrophic, and failing, porcine and human myocardium using histochemical, biochemi cal, and biophysical approaches. Measurements of contractile function at the myocyte level will be correlated with in vivo global cardiac function. Since changes in regional mechanical function in myocardium are thought to be precursors for the development of arrhythmias, an important goal of my research will be to investigate the mechanisms by which changes in regional cellular contractile function contribute to the development of arrhythmias at the whole organ level. These studies will fill an

7 8 important void in the literature since the mechanisms linking electrophysiological and mechanical dysfunction in heart failure are not clearly defined. Knowledge of the interaction between electrical and mechanical function at the cellular level is critical for understanding the complex processes that govern the development cardiac dysfunction and essential for devising more effective resynchronization therapies to treat heart failure patients with hypertrophic cardiomyopathy, arrhythmia, and abnormal contractile function, as well as identifying novel targets for gene therapy. Functional Role of Myosin Binding Protein-C in Myocardial Contraction In previous studies I have focused on characterizing the role of thick filament accessory proteins, especially myosin binding protein-c (cmybp-c) in modulating the contractile properties of the heart. Unlike the more established roles of thin filament accessory proteins and Ca 2+ in initiating contraction and activating the thin filament so that myosin cross-bridges can bind and undergo cycles of force generation, the roles of thick filament accessory proteins in modulating striated muscle contraction are less certain. Despite this, mutations in cmybp-c are among the most common, accounting for >45% of all mutations linked to inherited cardiomyopathies. Therefore, a research interest of my lab will be to define cmybp-c interactions with myosin and to determine the importance of these interactions to cardiac contractile properties. My initial studies on cardiac muscle focused on elucidating the functional role of myosin binding protein-c (cmybp-c) in cardiac muscle contraction using transgenic mouse models. These studies showed that cmybp-c is not just a structural protein but plays an important regulatory role in cardiac muscle contraction. I found that increases in contractility observed with beta adrenergic stimulation in vivo are due mostly to phosphorylation of cmybp-c. Specifically, beta adrenergic-induced protein kinase A (PKA) phosphorylation of cmybp -C accelerates cross-bridge cycling kinetics such that the rate of pressure and force development during systole is dramatically enhanced. These findings challenged the conventional view that PKA phosphorylation of troponin I was responsible for augmented cardiac contractility with beta adrenergic stimulation and have amplified the interest of the research community in this protein. Future studies will focus on the functional role of cmybp-c and its phosphorylation in acute myocardial infarction and in the development and progression of chronic heart failure using a combination of genetic, molecular, biochemical, and translational approaches. Preliminary studies show that the status of cmybp-c phosphorylation has important clinical relevance, especially in human patients with chronic atrial fibrillation or acute bouts of myocardial ischemia. My preliminary studies have shown that decreased cmybp-c phosphorylation in these patients is correlated with depressed systolic function while the maintenance of cmybp-c phosphorylation minimizes contractile dysfunction and limits ischemic damage during infarction. These findings hold great promise for cmybp-c as a therapeutic cardioprotective target, however, the mechanisms by which cmybp-c phosphorylation confers cardioprotection during atrial fibrillation and myocardial infarction are poorly understood. These mechanisms will be investigated using transgenic mouse models that lack cmybp-c, and express non-phosphorylatable or constitutively hyperphosphorylated cmybp-c, as well as in myocardial samples from porcine and human hearts. Changes in signaling cascades and protein phosphorylation in the disease state will be correlated with contractile properties of single myocytes and measurements of in vivo echocardiography and dynamic functional measurements of pressure volume relationships at the whole organ level.