Mariappan Muthuchamy, Ph.D.
Education and Post-Graduate Training
B.S., Chemistry, 1980, Madurai Kamaraj University, India
M.S., Biochemistry, 1983, Madurai Kamaraj University, India
Ph.D., Biochemistry/Molecular Biology, 1991, Madurai Kamaraj University, India
Cardiac Muscle Contraction
The main goal of our laboratory is to understand the molecular mechanisms of cardiac muscle dynamics in normal and diseased states. Particularly our interests focus on the relationships between thin filament activation and crossbridge kinetics, and how the mechanotransduction signaling transmits to myofilament activation. We use multiple techniques, molecular, cellular, biochemistry, structural and biophysical, to obtain information on the fundamental regulatory mechanisms of cardiac muscle contraction. We have demonstrated that exchange of myofibrillar protein can be achieved via a single transgenic manipulation, since stoichiometry of myofibrillar protein is accurately maintained. Using this approach, the mutant contractile proteins are exchanged for endogenous proteins in the mouse heart. Cardiac function is measured by work-performing heart preparations or by echocardiogram, and force/calcium is measured at the myofilament level. We have recently established that using the combined Atomic Force Microscopy (AFM) and fluorescence microscopy technologies, quantitative information on the interaction of mechanical forces with integrins-extracellular matrix protein bonds could be obtained. This has allowed us to study the mechanotransduction mechanisms in cardiomyocytes.
Lymphatic Muscle Contraction
In addition, our laboratory is interested in understanding the regulatory mechanisms of the lymphatic muscle contraction. The lymphatics normally transport fluids and proteins against net hydrostatic pressure and protein gradients. Lymphatic muscle has strong/phasic contractions, much higher shortening velocities and different intracellular calcium dynamics. The lymphatic muscle contractile characteristics indicate that the lymphatic pump acts similar to the heart in its generation of flow. We have shown that lymphatics from different regions of the body exhibited significant functional and contractile differences; in addition lymphatic muscle has a unique combination of smooth and striated muscle components that fit the multi-functional roles of the lymphatic vessels. We investigate the roles of regulatory proteins in lymphatic muscle contraction by using isolated vessel preparations from rat mesenteric and thoracic duct lymphatics along with pharmacological and siRNA approaches. Furthermore we use mouse embryoid body model to address the mechanisms of lymphatic vessel development. Understanding the mechanisms of lymphatic muscle biology is extremely important to ongoing attempts to better understand the lymphatic function and to discover the pathogenesis and the effective treatment of different forms of lymphedema.
von der Weid PY, Muthuchamy M. Regulatory mechanisms in lymphatic vessel contraction under normal and inflammatory conditions. Pathophysiology. 2010 Sep;17(4):263-276. PMID: 19945830
Wu X, Sun Z, Foskett A, Trzeciakowski JP, Meininger GA, Muthuchamy M. Cardiomyocyte contractile status is associated with differences in fibronectin and integrin interactions. Am J Physiol Heart Circ Physiol. 2010 Jun;298(6):H2071-H2081. PMID: 20382852; PMCID: PMC2886644
Wu X, Chakraborty S, Heaps CL, Davis MJ, Meininger GA, Muthuchamy M. Fibronectin increases the force production of mouse papillary muscles via a5b1 integrin. J Mol Cell Cardiol. 2011 JAN;50(1):203-213. PMID: 20937283; PMCID:PMC3019265
Chakraborty S, Nepiyushchikh ZV, Davis MJ, Zawieja DC, Muthuchamy M. Substance P activates both contractile and inflammatory pathways in lymphatics through the neurokinin receptors NK1R and NK3R. Microcirculation 2011 Jan;18(1):24-35. doi: 10.1111/j.1549-8719.2010.00064.x. PMID: 21166923; PMCID:PMC3058475.
Chakraborty S, Zawieja S, Wang W, Zawieja DC, Muthuchamy M. Lymphatic system: a vital link between metabolic syndrome and inflammation. Ann N Y Acad Sci. 2010 Oct;1207 Suppl 1:E94-E102. doi: 10.1111/j.1749-6632.2010.05752.x. PMID: 20961312; PMCID: PMC2965625
Sarin V, Muthuchamy M, Heaps CL. Ca2+ sensitization of cardiac myofilament proteins contributes to exercise training-enhanced myocardial function in a porcine model of chronic occlusion. Am J Physiol Heart Circ Physiol 2011 Oct;301(4):H1579-H1587. PMID: 21856915; PMCID:PMC3197372 [Available on 2012/10/1
Nepiyushchikh ZV, Chakraborty S, Wang W, Davis MJ, Zawieja DC1, Muthuchamy M1. Differential effects of myosin light chain kinase inhibition on contractility, force development and myosin light chain 20 phosphorylation of rat cervical and thoracic duct lymphatics. J Physiol. 2011 Nov 15;589(Pt 22):5415-5429. PMID: 21930597; PMCID: PMC3240881 [Available on 2012/11/15]
Kim J, Jayaprakasha GM, Muthuchamy M, Patil BS. Structure-function relationships of citrus limonoids on p38 MAP kinase activity in human aortic smooth muscle cells. Eur J Pharmacol. 2011 Nov 16;670(1):44-49. PMID: 21924259
Foskett AM, Ezekiel UR, Trzeciakowski JP, Zawieja DC, Muthuchamy M. Hypoxia and extracellular matric proteins influence angiogenesis and lymphangiogenesis in mouse embryoid bodies. Front Physiol. 2011;2:103. PMID: 22194726; PMCID: PMC3243103
Zawieja SD, Wang W, Wu X, Nepiyushchikh ZV, Zawieja DC, Muthuchamy M. Impairments in the intrinsic contractility of mesenteric collecting lymphatics in a rat model of metabolic syndrome. Am J Physiol Heart Circ Physiol 2012 Feb;302(3):H643-H653. PMID: 22159997