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Tupling, A. Russell

Russ Tupling photo Russ Tupling

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Research:

In all muscle cells, the sarcoplasmic reticulum (SR) is the major organelle that is responsible for the regulation of intracellular free calcium ([Ca2+]f). SR dysfunction, resulting in impaired muscle contractility, occurs under conditions of oxidative stress such as strenuous physical activity, ischemia-reperfusion, hyperthermia, aging and disease. The long term objectives of research in our laboratory are to understand the molecular and biochemical control mechanisms of Ca2+ regulation by the SR in muscle and to understand how defects in SR function that occur with oxidative stress contribute to the pathophysiology of fatigue, weakness and disease.

A primary area of research focus is examining the acute and chronic regulation of the SR Ca2+-ATPase or Ca2+ pump in response to oxidative stress. The SR Ca2+ pump is highly susceptible to oxidative damage and inactivation by reactive oxygen and nitrogen species; however, our studies examining the effects of exercise on SR Ca2+ pump function have suggested that potential cellular mechanisms exist that can prevent inactivation of the Ca2+ pump during oxidative stress. One possibility is that heat shock protein 70 (HSP70), which is induced by oxidative stress, can physically interact with the Ca2+ pump protein thus preserving the structural integrity and function of the Ca2+ pump during oxidative stress. In order to explore this possibility, we are currently employing a number of different model systems (SR membrane fractions, isolated myoblasts, in vivo) to examine both the physical and functional interaction between HSP70 and the SR Ca2+ pump expressed in both skeletal and cardiac muscle. The general approach is to compare the effects of acute oxidative stress on Ca2+ pump structure and function, cellular Ca2+ homeostasis and cellular contractile function between cells that over-express HSP70 and control or wild-type cells. For these studies we use recombinant DNA technology to over-express HSP70 in isolated myoblasts and exposure to either a mild heat shock or single exercise bout to physiologically induce over-expression of HSP70 in vivo. Ultimately, these studies may help to explain the cytoprotective effects of HSP70 in all cells which could lead to the development of more effective treatment strategies for diseases like cancer and heart disease.

Another area of research of major interest in our laboratory is examining the genetic/ physiological determinants of metabolic rate and obesity. We are currently facing an ‘obesity epidemic’ worldwide. It can be argued that behavioural and environmental factors leading to reduced activity levels and increased caloric intake are at the root of the problem; however, individual susceptibility to obesity related to the regulation of energy balance is also a critical factor that is important to understand if we are to develop successful prevention and/ or treatment strategies for obesity. The SR Ca2+ pump requires energy in the form of ATP to pump Ca2+ from the cytosol into the SR. We estimate that the SR Ca2+ pump could account for as much as 10 – 30% of total daily energy expenditure. A fundamental question is whether variations in the efficiency of SR Ca2+ transport can explain variations in metabolic rate between individuals. Currently, we are developing research strategies aimed at altering the efficiency of SR Ca2+ transport in muscle cells and other cells in the body and we will assess the related phenotypic alterations to metabolic rate and susceptibility to obesity.

Key Publications:

  1. Tupling, A.R., E. Bombardier, R.D. Stewart, C. Vigna and A.E. Aqui (2007). Muscle fiber type specific response of Hsp70 expression in human quadriceps following acute isometric exercise. J. Appl. Physiol. 103: 2105-11.
  2. Tupling, A.R., C. Vigna, R.J. Ford, S.C. Tsuchiya, D.A. Graham, S.G. Denniss and J.W. Rush (2007). Effects of Buthionine Sulfoximine (BSO) Treatment on Diaphragm Contractility and SR Ca2+ Pump Function in Rats. J. Appl. Physiol. 103: 1921-28.
  3. Tupling, A.R., A.O. Gramolini, T.A. Duhamel, H. Kondo, M. Asahi, S.C. Tsuchiya, M.J. Borrelli, J.R. Lepock, K. Otsu, M. Hori, D.H. MacLennan and H.J. Green (2004). HSP70 binds to the fast-twitch skeletal muscle Sarco (endo)plasmic reticulum Ca2+-ATPase (SERCA1a) and prevents thermal inactivation. J. Biol. Chem. 279: 52382 – 9.
  4. Tupling A. R. (2004). The sarcoplasmic reticulum in fatigue and disease. Can. J. Appl. Physiol. 29(3): 308-29.
  5. Tupling, A.R., M. Asahi and D.H. MacLennan (2002). Sarcolipin over-expression in rat slow-twitch muscle inhibits sarcoplasmic reticulum Ca2+ uptake and impairs contractile function. J. Biol. Chem. 277(47): 44740 – 44746.