Mayo Graduate School, 2001
Muscle physiology - the effects of exercise and age on muscle metabolism and insulin resistance; type II diabetes
Insulin resistance is a key feature in the pathogenesis of type II diabetes and is associated with a number of pathological states including obesity, dyslipidemia, hyperinsulinemia, hypertension and cardiovascular disease. This combination of disease states is often referred to as "syndrome X" or the insulin resistance syndrome. It is well established that exercise has important health benefits for individuals with type II diabetes. Skeletal muscle is the major tissue responsible for total body glucose disposal and regular exercise has the ability to enhance glucose transport and insulin action in working skeletal muscles. Despite the physiological importance of exercise in regulating glucose homeostasis, the underlying molecular mechanism of this phenomenon is poorly understood.
Insulin and muscle contractile activity induce skeletal muscle glucose transport through distinct signaling pathways. GLUT 4 is the major glucose transport isoform in skeletal muscle and translocation of GLUT4 from inside the cell to the plasma membrane is the major mechanism by which both insulin and muscle contractions increase glucose transport. While insulin stimulated glucose transport is impaired in individuals with type II diabetes, contraction induced glucose transport is not. As a result, exercise functions as a clinically relevant alternative pathway for glucose disposal in conditions of insulin resistance.
Diabetes in the elderly is emerging as one of the most important health problems of the 21st century. The ability of insulin to regulate glucose homeostasis declines with age and recent studies have shown that habitual endurance exercise does not prevent the age-associated decline in insulin action in skeletal muscle. This raises the question of whether there is a defect in the contraction-mediated glucose transport pathway with age that is not present in other insulin resistant conditions. The state of insulin resistance in the elderly is further complicated by the increase in oxidative stress associated with aging. Recent evidence suggests that a heightened state of oxidative stress, and a concomitant decrease in antioxidants, contributes to the development of insulin resistance. My research examines the interaction of exercise and age on the development of insulin resistance in skeletal muscle by asking the following questions: 1) Is the age-associated decline in insulin action a function of limited exercise capacity (i.e. reduced blood flow and a decrease in muscle protein mass with age) or a defect in the glucose transporter function of skeletal muscle? 2) What is the role of oxidative stress in the development of skeletal muscle insulin resistance? In addition, the use of antioxidants as potential therapeutic agents against the age-associated increase in insulin resistance will be investigated.
Wright, D.C., P.C. Geiger, J.O. Holloszy, and D.H. Han. Contraction-and hypoxia mediated glucose transport is mediated by a Ca 2+ dependent mechanism in slow-twitch rat soleus muscle. Am J Physiol Endocrinol Metab, 288(6):E1062-6, 2005.
Geiger, P.C., D.C. Wright, D.H. Han, and J.O. Holloszy. Activation of p38MAP kinase enhances sensitivity of muscle glucose transport to insulin. Am J Physiol Endocrinol Metab, 288:E782-788, 2005.
Wright, D.C., P.C. Geiger, D.H. Han, and J.O. Holloszy. Phorbol Esters Effect Skeletal Muscle Glucose Transport in a Fiber Type Specific Manner. Am J Physiol Endocrinol Metab, 287:E305-309, 2004.
Bagni, M.A., B. Colombini, P.C. Geiger, R. Berlinguer Palmini, and G. Cecchi. A non cross-bridge calcium-dependent stiffness in frog muscle fibers. Am J Physiol Cell Physiol, 286(6): C1353-1357, 2004.
Bagni, M.A., B. Colombini, F. Colomo, P. Geiger, R.B. Palmini, G. Cecchi. Force response to stretches in activated frog muscle fibers at low tension. Adv Exp Med Biol, 538:429-38; discussion 438-9, 2003.
Geiger, P.C., J.P. Bailey, W.Z. Zhan, C.B. Mantilla, and G.C. Sieck. Denervation-induced changes in myosin heavy chain expression in the rat diaphragm muscle. J Appl Physiol, 95:611-619, 2003.
Han, Y.S., P.C. Geiger, M.J. Cody, R.L. Macken, and G.C. Sieck. ATP Consumption rate per cross bridge depends on myosin heavy chain isoform. J Appl Physiol, 94: 2188-2196, 2003.
Sieck, G.C., Y.S. Prakash, Y.S. Han, Y.H. Fang, P.C. Geiger, and W.Z. Zhan. Changes in actomyosin ATP consumption rate in rat diaphragm muscle fibers during postnatal development. J Appl Physiol 94(5): 1896-1902, 2003.
Geiger, P.C., M.J. Cody, Y.S. Han, L.W. Hunter, W.Z. Zhan, and G.C. Sieck. Effects of hypothyroidism on maxiumum specific force in rat diaphragm muscle fibers. J Appl Physiol 92(4): 1506-1514, 2002.
Heunks, L.M.A., M.J. Cody, P.C. Geiger, P.N.R. Dekhuijzen, and G.C. Sieck. Nitric oxide impairs calcium activation and slows cross-bridge cycling kinetics in skeletal muscle. J Appl Physiol 91: 2233-2239, 2001.
Geiger, P.C., M.J. Cody, R.L. Macken, and G.C. Sieck. Effect of unilateral denervation on maximum specific force in rat diaphragm muscle fibers. J Appl Physiol 90(4): 1196-1204, 2001.
Han, Y.S., D.N. Proctor, P.C. Geiger, and G.C. Sieck. Reserve capacity for ATP consumption during isometric contraction in human skeletal muscle fibers. J Appl Physiol 90(2): 657-664, 2001.
Geiger, P.C., M.J. Cody, R.L. Macken, M.E. Bayrd, Y.H. Fang, and G.C. Sieck. Selected Contribution: Mechanisms underlying increased force generation by rat diaphragm muscle fibers during development. J Appl Physiol 90(1): 380-388, 2001.
Geiger, P.C., M.J. Cody, R.L. Macken, and G.C. Sieck. Maximum specific force depends on myosin heavy chain content in rat diaphragm muscle fibers. J Appl Physiol 89(2): 695-703, 2000.
Geiger, P.C., M.J. Cody, and G.C. Sieck. Force-Calcium relationship depends on myosin heavy chain and troponin isoforms in rat diaphragm muscle fibers. J Appl Physiol 87(5): 1894-1900, 199.