CSEP Member Contributions to the understanding of physiology: a focus on molecular biology approaches

December 11, 2010

The Canadian Society for Exercise Physiology will be celebrating its 50th anniversary in 2017. A signature initiative is a celebration of the contributions of Canadian researchers to exercise physiology over the past 50 years. The objective is to highlight significant Canadian contributors and their contributions to exercise physiology, health and fitness, nutrition and gold standard publications globally as well as provide insights on future research directions in these areas. These achievements have been organized into a series of short historical communiqués on prominent Canadian contributors and will be published on a monthly basis.

CSEP Member Contributions to the understanding of physiology: a focus on molecular biology approaches

Ljubicic V¹, Belcastro AN², Gurd BJ³, Joanisse DR⁴, Safdar A⁵, Tryon LD⁶, Hood DA ^6,*.

¹ Department of Kinesiology, McMaster University, Hamilton, Ontario, Canada
² School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada
³ School of Kinesiology and Health Studies, Queen’s University, Kingston, Ontario, Canada
⁴ Department of Kinesiology, Université Laval, Québec, Québec, Canada
⁵ Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada⁶ Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada

 

The vision of the Canadian Society for Exercise Physiology (CSEP) is to achieve “excellence in exercise physiology and health and fitness through research and best practice”. In order to accomplish this from a research perspective, numerous approaches must be used. Over the last 50 years, molecular biology tools have been increasingly employed to help us understand the mechanisms underlying the health benefits of exercise. Here we review some of the key CSEP contributors who have used molecular biology methods to advance our knowledge of the effects of exercise on whole body fitness and health.

Dr. Claude Bouchard

Since his first publication over fifty years ago, Dr. Claude Bouchard has been prolific in his publication of research in obesity and exercise sciences, with a specific focus on genetics and adaptation. Further, Dr. Bouchard has been at the forefront of notable large scale studies, including the Quebec Family Study (QFS), and the HERITAGE Family Study. Both studies were started while at Université Laval in Quebec City, where he founded what is today the Department of Kinesiology.

A large part of his body of work has focused on the genetic contribution to indicators of fitness and human trainability. During his career, he has pioneered the use of monozygotic twin pairs in experimental designs in which a given treatment is applied to both members of each pair, allowing testing for the presence of genotype-treatment interaction effects. He has successfully applied this approach in exercise, overfeeding and negative energy balance studies (Bouchard et al. 1986). Dr. Bouchard has also authored a number of papers highlighting the genetics which determine submaximal and maximal cardiorespiratory fitness indicators (Lortie et al. 1982). His research has also demonstrated an important genetic component in the heterogeneity of human responses to standardized and fully monitored exercise training programs (Bouchard 1983). These genetic contributions were shown to apply not only to cardiorespiratory fitness phenotypes, but also to changes in common cardiometabolic risk factors in response to exercise training (Tremblay et al. 1987).

Technological advances have since allowed his work to expand into the molecular and genomic bases of human exercise responsiveness, helping to identify genomic predictors of trainability and pathways and networks driving the response to exercise training (Bouchard et al. 2000). He remains extremely active today at the Human Genomic Laboratory at the Pennington Biomedical Centre, having recently started exploring the adverse response phenotypes and the lack of responsiveness to an exercise regimen that are observed in some individuals (Bouchard et al. 2012).

Dr. Arend Bonen

During his time as a professor at Dalhousie University and the University of Waterloo, and as a Canada Research Chair in Metabolism and Health at the University of Guelph, Dr. Arend Bonen used a combination of molecular biology and physiology techniques to help shape our understanding of when, how and why our muscles utilize carbohydrates and fats.

In the 90’s the Bonen lab demonstrated the importance of transporter mediated control of glucose (Johannsson et al. 1996), and lactate (Bonen 2000) metabolism in skeletal muscle. Subsequently, Dr. Bonen, in collaboration with a group from The Netherlands, demonstrated that fatty acid uptake by muscle was also a highly regulated, protein mediated process (Bonen et al. 1998). These latter findings laid the foundation for a series of studies published by Dr. Bonen and his collaborators that changed our understanding of how fatty acid transport contributes to the regulation of skeletal and cardiac muscle fat metabolism in health and disease (Glatz et al. 2010). The Bonen lab contributed to these collaborations by demonstrating how skeletal muscle fatty acid transporter expression (Benton et al. 2008) and cellular localization are regulated, and how fatty acid transport contributes to fatty acid uptake, mitochondrial substrate metabolism and the development of disease states associated with obesity and diabetes.

The research performed within Arend Bonen’s labs demonstrated that substrate uptake by skeletal muscle is mediated by transport proteins that are highly regulated. These results have changed the way we understand the control of skeletal muscle metabolism and continue to inform current research on skeletal muscle metabolism in health and disease.

Dr. Mark A. Tarnopolsky

While the positive effects of exercise are well-established, the underlying molecular mechanisms that mediate multisystem cross-talk and modulate the pro-metabolic effects of exercise have yet to be fully unraveled. As a leader in the field of molecular exercise physiology, Dr. Mark A. Tarnopolsky has dedicated his career beginning to understand these mechanisms. Dr. Tarnopolsky currently holds multiple positions at the Hamilton Health Sciences Foundation in Neuromuscular Disorders, McMaster University’s Michael G. DeGroote School of Medicine, and at the Corkins and Lammert Neurometabolic and Neuromuscular Clinic.

Over the course of his career, Dr. Tarnopolsky’s group has conducted seminal basic and clinical studies to unravel the physiology and molecular biology of exercise. His research group, in collaboration with national and international peers, has authored countless peer-reviewed publications that provide crucial insight into the molecular adaptations of various forms of exercise, including endurance, resistance, and high-intensity interval training. As a researcher and clinician, he has been particularly interested in the relationship that these modes of exercise have with systemic mitochondrial biogenesis, mtDNA genomic stability, metabolic and redox homeostasis, and reduced incidence of co-morbidities associated with aging and rare genetic disorders (Gibala et al. 2006, Melov et al. 2007, Safdar et al. 2011, 2016a). Recently, Dr. Tarnopolsky’s group has been interested in the utility of “exosomes” to ameliorate disease, or to facilitate the metabolic adaptations to exercise. He has coined the term “exerkines” to describe the humoral factors that are released from all tissues and organs, and mediate the systemic benefits of exercise. His laboratory is currently examining the role of exosomes as delivery vehicles of these exerkines (Safdar et al. 2016b). His long-term vision is to utilize cutting-edge developments in molecular biology, -omics technologies, and bioinformatics to further enhance our understanding of the complex relationship between human health and the various forms of exercise while considering the interactive influence of genetics, epigenetics, and nutrition.

Dr. Angelo Belcastro

During his tenure at the School of Rehabilitation Medicine at the University of British Columbia and the School of Kinesiology at the University of Western Ontario, Dr. Angelo Belcastro has led innovative work in the study of organelle-specific protein cleavage and breakdown mediated by the calcium-activated neutral protease system [calpain; CAPN1/2] in striated muscle. His work has increased our knowledge of the importance of calpain’s targeted action on protein breakdown during periods of altered muscle activity. Dr. Belcastro’s laboratory first showed that during muscle growth the calcium regulated processes of the SR and contractile proteins are impacted by different levels of muscle activity and inactivity (Belcastro and Wenger 1982). Moreover, the changes in intracellular calcium accompanying an acute bout of increased contractile activity were associated with dramatic changes in the ultrastructure of several organelles (SR, mitochondria, myofibrils and sarcomeres)(Gilchrist et al. 1992, Belcastro et al. 1993). Dr. Belcastro provided the first evidence for a link between the calcium imbalance and ultrastructure changes by reporting that calpain was activated and redistributed in muscle with exercise (Arthur et al. 1999).

Collectively, his early work has led to the Calcium-Calpain Hypothesis to explain losses in muscle structure and function with exercise and/or disease (Belcastro et al. 1998, Raastad et al. 2010). As a result of Dr. Belcastro’s work, the knowledge gained about calpain’s role in muscle organelle assembly/disassembly, protein breakdown/release and protein degradation with exercise has been extended to include other metabolically challenged and disease states where there is a loss and/or change of muscle function.

As we all know, mitochondria are cellular organelles referred to as the “powerhouses” of the cell. Since beginning his Cell Physiology Laboratory at York University in 1988, Dr. David A. Hood and his team have dramatically expanded knowledge on the critical importance of these organelles in mediating skeletal muscle health and disease, as well as how mitochondria respond and adapt to changes in muscle activity with exercise, inactivity and aging.

Dr. David Hood

As a Canada Research Chair at York University, Dr. Hood’s research has focused on delineating the cellular biology of adaptations that occur with exercise or aging, with specific focus on the function, biogenesis and degradation of the mitochondrion. His goal of understanding the fundamental mechanisms by which physical activity regulates the structure, function and dynamics of this organelle has led him to pursue the study of several signaling molecules, such as PGC-1α, p53 and SIRT1 (Ljubicic et al. 2010, Hood et al. 2015), and to examine the means through which these key metabolic regulators modulate the adaptation to exercise and/or aging. In line with this, the Hood Laboratory has detailed many cellular processes that comprise exercise- and aging-induced changes to mitochondrial content in skeletal muscle including, but not limited to, intracellular signalling and gene expression (Ljubicic et al. 2010, Hood et al. 2015), protein trafficking and import (Hood et al. 2003), organelle dynamics (Iqbal and Hood 2015) and mitochondrial specific degradation (mitophagy) (Vainshtein and Hood 2016). The long term goal of this work is to use this foundation of discoveries to effect positive change in individuals with numerous chronic metabolic and neuromuscular conditions, which are believed to be of mitochondrial origin. His success in the field of muscle metabolism research prompted Dr. Hood to found the Muscle Health Research Centre (MHRC) at York University in 2009. This Centre has grown to incorporate over 20 Faculty and Adjunct members, and it strives to enable the integrated study of muscle biology using a diversity of molecular and whole-body methods.

This brief summary of key CSEP member contributions to the molecular biology of exercise adaptations is not all-inclusive. Indeed, a growing number of trainees are now embracing the use of molecular biology tools to understand the fundamental mechanisms which underlie the health benefits of exercise. This bodes well for future growth in this field.

References

Arthur, G.D., Booker, T.S., and Belcastro, A.N. 1999. Exercise promotes a subcellular redistribution of calcium-stimulated protease activity in striated muscle. Can. J. Physiol. Pharmacol. 77(1): 42–7.

Belcastro, A.N., Gilchrist, J.S., and Scrubb, J. 1993. Function of sksletal muscle sarcoplasmic reticulum vesicles with exercise. J. Appl. Physiol. 75(6): 2412–2418.

Belcastro, A.N., Shewchuk, L.D., and Raj, D.A. 1998. Exercise-induced muscle injury: A calpain hypothesis. Mol. Cell. Biochem. 179: 135–145.

Belcastro, A.N., and Wenger, H. 1982. Myofibril and sarcoplasmic reticulum changes with exercise and growth. Eur J Appl Physiol 49: 87–95.

Benton, C.R., Nickerson, J.G., Lally, J., Han, X.X., Holloway, G.P., Glatz, J.F.C., Luiken, J.J.F.P., Graham, T.E., Heikkila, J.J., and Bonen, A. 2008. Modest PGC-1α overexpression in muscle in vivo is sufficient to increase insulin sensitivity and palmitate oxidation in subsarcolemmal, not intermyofibrillar, mitochondria. J. Biol. Chem. 283(7): 4228–4240.

Bonen, A. 2000. Lactate transporters (MCT proteins) in heart and skeletal muscles. Med. Sci. Sports Exerc. 32(4): 778–789.

Bonen, A., Luiken, J.J.F.P., Liu, S., Dyck, D.J., Kiens, B., Kristiansen, S., Turcotte, L.P., Van Der Vusse, G.J., and Glatz, J.F.C. 1998. Palmitate transport and fatty acid transporters in red and white muscles. Am. J. Physiol. 275(38): E471–8.

Bouchard, C. 1983. Human adaptability may have a genetic basis. In Health Risk Estimation, Risk Reduction and Health Promotion. Proceedings of the 18th Annual Meeting of the Society of Prospective Medicine. Edited by F. Landry. Canadian Public Health Association, Ottawa. pp. 463–476.

Bouchard, C., Blair, S.N., Church, T.S., Earnest, C.P., Hagberg, J.M., H??kkinen, K., Jenkins, N.T., Karavirta, L., Kraus, W.E., Leon, A.S., Rao, D.C., Sarzynski, M.A., Skinner, J.S., Slentz, C.A., and Rankinen, T. 2012. Adverse metabolic response to regular exercise: Is it a rare or common occurrence? PLoS One 7(5): 1–9. doi:10.1371/journal.pone.0037887.

Bouchard, C., Lesage, R., Lortie, G., Simoneau, J.A., Hamel, P., Boulay, M.R., Pérusse, L., Thériault, G., and Leblanc, C. 1986. Aerobic performance in brothers, dizygotic and monozygotic twins.

Bouchard, C., Rankinen, T., Chagnon, Y.C., Rice, T., Pérusse, L., Gagnon, J., Borecki, I., An, P., Leon, A.S., Skinner, J.S., Wilmore, J.H., Province, M., and Rao, D.C. 2000. Genomic scan for maximal oxygen uptake and its response to training in the HERITAGE Family Study. J. Appl. Physiol. 88(2): 551–559.

Gibala, M.J., Little, J.P., van Essen, M., Wilkin, G.P., Burgomaster, K.A., Safdar, A., Raha, S., and Tarnopolsky, M.A. 2006. Short-term sprint interval versus traditional endurance training: similar initial adaptations in human skeletal muscle and exercise performance. J. Physiol. 575(3): 901–911.

Gilchrist, J.S., Wang, K.K., Katz, S., and Belcastro, A.N. 1992. Calcium-activated neutral protease effects upon skeletal muscle sarcoplasmic reticulum protein structure and calcium release. J. Biol. Chem. 267(29): 20857–65.

Glatz, J.F.C., Luiken, J.J.F.P., and Bonen, A. 2010. Membrane fatty acid transporters as regulators of lipid metabolism : Implications for metabolic disease. Physiol. Rev. 90: 367–417.

Hood, D.A., Adhihetty, P.J., Colavecchia, M., Gordon, J.W., Irrcher, I., Joseph, A.-M., Lowe, S.T., and Rungi, A.A. 2003. Mitochondrial biogenesis and the role of the protein import pathway. Med. Sci. Sports Exerc. 35(1): 86–94.

Hood, D.A., Tryon, L.D., Vainshtein, A., Memme, J., Chen, C., Pauly, M., Crilly, M.J., and Carter, H. 2015. Exercise and the Regulation of Mitochondrial Turnover. Prog. Mol. Biol. Transl. Sci. 135: 99–127.

Iqbal, S., and Hood, D.A. 2015. The role of mitochondrial fusion and fission in skeletal muscle function and dysfunction. Front. Biosci. 20: 157–172.

Johannsson, E., McCullagh, K.J., Han, X.X., Fernando, P.K., Jensen, J., Dahl, H.A., and Bonen, A. 1996. Effect of overexpressing GLUT-1 and GLUT-4 on insulin- and contraction-stimulated glucose transport in muscle. Am J Physiol 271(3 Pt 1): E547–55.

Ljubicic, V., Joseph, A.-M., Saleem, A., Uguccioni, G., Collu-Marchese, M., Lai, R.Y.J., Nguyen, L.M.-D., and Hood, D.A. 2010. Transcriptional and post-transcriptional regulation of mitochondrial biogenesis in skeletal muscle: effects of exercise and aging. Biochim. Biophys. Acta 1800(3): 223–34. Elsevier B.V.

Lortie, G., Bouchard, C., Leblanc, C., Tremblay, A., Simoneau, J.A., Theriault, G., and Savoie, J.P. 1982. Familial similarity in aerobic power. Hum. Biol. 54(4): 801–812.

Melov, S., Tarnopolsky, M.A., Beckman, K., Felkey, K., and Hubbard, A. 2007. Resistance exercise reverses aging in human skeletal muscle. PLoS One 2(5): e465.

Raastad, T., Owe, S.G., Paulsen, G., Enns, D., Overgaard, K., Crameri, R., Kiil, S., Belcastro, A., Bergersen, L., and Hallen, J. 2010. Changes in calpain activity, muscle structure, and function after eccentric exercise. Med. Sci. Sports Exerc. 42(1): 86–95.

Safdar, A., Bourgeois, J.M., Ogborn, D.I., Little, J.P., Hettinga, B.P., Akhtar, M., Thompson, J.E., Melov, S., Mocellin, N.J., Kujoth, G.C., Prolla, T.A., and Tarnopolsky, M.A. 2011. Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice. Proc. Natl. Acad. Sci. U. S. A. 108(10): 4135–40. doi:10.1073/pnas.1019581108.

Safdar, A., Khrapko, K., Flynn, J.M., Saleem, A., De Lisio, M., Johnston, A.P.W., Kratysberg, Y., Samjoo, I.A., Kitaoka, Y., Ogborn, D.I., Little, J.P., Raha, S., Parise, G., Akhtar, M., Hettinga, B.P., Rowe, G.C., Arany, Z., Prolla, T.A., and Tarnopolsky, M.A. 2016a. Exercise-induced mitochondrial p53 repairs mtDNA mutations in mutator mice. Skelet. Muscle 6(7): 1–17. Skeletal Muscle.

Safdar, A., Saleem, A., and Tarnopolsky, M.A. 2016b. The potential of endurance exercise-derived exosomes to treat metabolic diseases. Nat Rev Endocrinol (May). Nature Publishing Group.

Tremblay, A., Poehlman, E., Nadeau, A., Perusse, L., and Bouchard, C. 1987. Is the response of plasma glucose and insulin to short-term exercise-training genetically determined? Horm. Metab. Res. 19: 65–67.

Vainshtein, A., and Hood, D.A. 2016. The regulation of autophagy during exercise in skeletal muscle. J. Appl. Physiol. 120(6): 664–673.

*To whom correspondence should be addressed:

David A. Hood, PhD
School of Kinesiology and Health Science,
Farquharson
Life Science Building, Rm 302
York University, Toronto, ON
M3J 1P3, Canada
Tel: (416) 736-2100 ext. 66640
Email: dhood@yorku.ca