Exercise physiology

Our laboratory studies cellular and tissue injury due to oxidative stress. We pioneered the discovery that cells surviving oxidative stress develop hypertrophy. This discovery has been validated in many cell types as a consequence of cellular stress and survival response. Enlarged cells contribute to loss of functionality during the development of diseases. In the myocardium, cardiomyocyte hypertrophy can be detected as a result of ischemic injury and contributes to heart failure. Continuing on the investigation of mechanisms of cell survival has led us to focus on cellular defense system. From our many years of comprehensive and systematic studies on cellular and molecular events initiated by oxidative stress, Nrf2 stands out as the key controller for cell defenses. We have made several discoveries in recent years, including 1) oxidative stress induced de novo Nrf2 protein translation; 2) Nrf2 physically interacts with mitochondria and protects mitochondria against oxidative stress induced decay; and 3) deficiency in Nrf2 sensitizes the myocardium to ischemic injury.

The research goal of my laboratory is to understand the molecular motions and interactions of proteins involved in regulating contractile function of healthy cardiac and skeletal muscle, to determine the culprits of contractile dysfunction and remodeling in muscle disorders and cardiovascular disease, and then apply these insights to design novel therapies. We use biophysical approaches, such as time-resolved spectroscopy with site-directed probes to assess protein structural dynamics and mechanical measurements of isolated muscle fibers to assess contractile force and kinetics, in order to establish structure-function relationships inherent to the molecular, biochemical, and physiological mechanisms.

Timothy Secomb, PhD, studies the microcirculation, a network of extremely small blood vessels that supply oxygen and nutrients to all parts of our tissues. The focus of work in his research group is the use of mathematical and computational approaches to study blood flow and mass transport in the microcirculation. Working in collaboration with experimentalists, the aim is to understand quantitatively the processes involved. Dr. Secomb examines the relationship between red blood cell mechanics and flow resistance in microvessels. Theoretical predictions agree well with observations in glass tubes, but resistance is higher living tissue. The major cause is the presence of a relatively thick macromolecular lining (endothelial surface layer) on the walls of microvessels. He also simulates oxygen exchange between networks of microvessels and surrounding tissues in skeletal muscle and tumors. In skeletal muscle, oxygen can be exchanged diffusively between arterioles and capillaries, and Dr. Secomb’s lab is studying the determinants of maximal oxygen consumption. In tumors, the relationship between network structure and occurrence of local hypoxic (radiation-resistant) regions is a source of curiosity. They are analyzing the delivery of chemotherapeutic drugs in tumor tissues, and developing improved models to describe the responses of tumor cells to chemotherapy and radiation. Models for the structural responses of microvessels to functional demands are being developed. Maintenance of a stable, functionally adequate distribution of vessel diameters can be achieved if each vessel responds to changes in wall shear stress, intravascular pressure and local metabolic conditions, and if mechanisms exist for information transfer upstream and downstream along flow pathways. Models for the active regulation of blood flow by changes in vascular tone are also being developed, taking into account vascular responses to wall shear stress, pressure and local metabolic state, and including effects of conducted responses along vessel walls. Another project in the group is the development of computer simulations for the dynamics of the left ventricle that can be run in real time and provide a tool for analysis of data derived from ultrasound echocardiography images.

The long-term goal of research in my lab is to understand the molecular mechanisms of muscle contraction. I am especially interested in how contractile proteins of muscle sarcomeres regulate the force and speed of contraction in the heart. The question is important from both basic science and clinical perspectives because mutations in sarcomere proteins of muscle are a leading cause of hypertrophic cardiomyopathy (HCM), the most common cause of sudden cardiac death in the young and a prevalent cause of heart failure in adults. Myosin binding protein-C (MyBP-C) is a muscle regulatory protein that speeds actomyosin cycling kinetics in response to adrenaline (b-adrenergic stimuli) and is one of the two most commonly affected proteins linked to HCM. Currently, the major research focus in my lab is understanding the mechanisms by which cMyBP-C regulates contractile speed and mechanisms by which mutations in cMyBP-C cause disease. In pursuing these interests I have established a variety of approaches to investigate muscle contraction at molecular, cellular, and whole animal levels. Methods include single molecule atomic force microscopy (AFM), mechanical force measurements in permeabilized muscle cells, in vitro motility assays, biochemical enzyme and binding assays, immunofluorescent imaging, knockout/transgenic animal models and the development of a natural large animal model of HCM.

Hendrikus Granzier, PhD, studies the mechanisms whereby the giant filamentous protein titin (the largest protein known) influence muscle structure and function. His lab has shown that titin functions as a molecular spring that mediates acute responses to changing pathophysiological states of the heart. They also study the role of titin in cardiac disease, using mouse models with specific modifications in the titin gene, including deciphering the mechanisms that are responsible for gender differences in diastolic dysfunction. An additional focus of Dr. Granzier’s lab is on nebulin, a major muscle protein that causes a severe skeletal muscle disease in humans. Based on previous work, they hypothesize that nebulin is a determinant of calcium sensitivity of contractile force. To test this and other concepts, he uses a nebulin knockout approach in the mouse. Research is multi-faceted and uses cutting-edge techniques at levels ranging across the single molecule, single cell, muscle, and the intact heart. His research group is diverse and has brought together individuals from several continents with expertise ranging from physics and chemistry to cell biology and physiology.