Dr. Graham Holloway

As a highly competitive athlete I have always been interested in understanding skeletal muscle physiology. In my Undergraduate degree at McMaster University this was more of idle curiosity, rather than a career path. However, when I was introduced to the research process and a larger understanding of skeletal muscle physiology during my masters training at the University of Waterloo, I immediately found a career I was interested in pursing. My interest in understanding how muscle utilizes substrates (carbohydrates and fats) during exercise was further strengthened during my PhD at the University of Guelph, as I became aware of the ability to apply general physiology to the study of various diseases. My research during my post-doctoral training, which has continued during my faculty position, has been focused on using exercise and nutritional approaches to identify novel regulation in mitochondrial bioenergetics (aerobic respiration), and apply this knowledge to the study of various diseases.

Hon B.Kin. - McMaster University
M.Sc. - University of Waterloo
Ph.D. - University of Guelph

My research is primarily focused on understanding the regulation of mitochondrial bioenergetics, with a particular interest in studying fatty acid oxidation (breakdown of fat yielding energy) in skeletal and cardiac muscle. I use a variety of techniques to examine mitochondrial function (isolated mitochondria, permeabilized fibres, whole muscle incubations), use molecular biological approaches to up-and down-regulate mitochondrial proteins, as well exercise, altered nutrition and aerobic training to study novel regulation in mitochondrial bioenergetics. We apply basic knowledge garnered from these studies to the study of human exercise performance as well as type 2 diabetes, heart failure, diabetic cardiomyopathy and various neuropathologies, conditions that have all been affiliated with alterations in mitochondria as a key event in the progression and/or development of the disease.

2018

Holloway GP, Holwerda A, Dirks ML, van Kranenburg J, and van Loon LJC. Age-Associated Impairments in Mitochondrial ADP Sensitivity Contribute to Redox Stress in Senescent Human Skeletal Muscle. Cell Reports, 22 (11): 2837-2848, 2018.

Miotto PM, McGlory C, Holloway TM, Phillips SM and Holloway GP. Sex-Differences in Mitochondrial Respiratory Function in Human Skeletal Muscle. Am. J. Physiol. Reg. Integr. Comp. Physiol., in press, 2018.

Miotto PM and Holloway GP. Exercise-Induced Reductions in Mitochondrial ADP Sensitivity Contribute to the Induction of Gene Expression and Mitochondrial Biogenesis Through Enhanced Mitochondrial H₂O₂ Emission. Mitochondrion, in press, 2018.

Monaco CMF, Miotto PM, Huber JS, van Loon LJC, Simpson JA and Holloway GP. Sodium Nitrate Supplementation Alters Mitochondrial H₂O₂ Emission but Does Not Improve Mitochondrial Oxidative Metabolism in the Heart of Healthy Rats. Am. J. Physiol. Reg. Integr. Comp. Physiol., in press, 2018.

Monaco CMF, Proudfoot R, Miotto PM, Herbst EAF, MacPherson REK and Holloway GP. Alpha-Linolenic Acid Supplementation Prevents Exercise-Induced Improvements in White Adipose Tissue Mitochondrial Bioenergetics and Whole-Body Glucose Homeostasis in Obese Zucker Rats. Diabetologia. 61(2): 433-444, 2018.

2017

Barbeau PA, Holloway TM, Whitfield J, Baechler B, Quadrilatero J, van Loon LJC, Chabowski A, and Holloway GP. α-Linolenic Acid and Exercise Training Independently, and Additively, Decrease Blood Pressure and Prevent Diastolic Dysfunction in Obese Zucker Rats. Journal of Physiology. 595(13): 4351-4364, 2017.

Holloway GP. Nutrition and Training Influences on the Regulation of Mitochondrial Adenosine Diphosphate Sensitivity and Bioenergetics. Sports Medicine. 47 (Suppl 1): 13-21, 2017.

Miotto PM, Horbatuk M, Proudfoot R, Matravadia S, Bakovic M, Chabowski A, and Holloway GP. Alpha-Linolenic Acid Supplementation and Exercise Training Reveal Independent and Additive Responses on Hepatic Steatosis in Obese Rats. Am. J. Physiol. Endocrinol. Metab. 312(6): E461-470, 2017.

Miotto PM, Steinberg GR, and Holloway GP. Controlling CPT-I M-CoA Sensitivity in Skeletal Muscle: The Importance of AMPK-Independent Regulation of Intermediate Filaments During Exercise. Biochemical Journal, 474(4): 557-569, 2017

Paglialunga S, Simnett G, Robson H, Pillai R, Arkell AM, Simpson JA, Bonen A, Joseph JW and Holloway GP. The Rab-GTPase Activating Protein, TBC1D1, is Critical for Maintaining Normal Glucose Homeostasis and b-Cell Mass. Submitted to Applied Physiology Nutrition and Metabolism. 42 (6): 647-655, 2017.

Whitfield J, Gamu D, Heigenhauser GJF, van Loon LJC, Spriet LL, Tupling AR and Holloway GP. Beetroot Juice Increases Human Muscle Force without Changing Ca₂+- Handling Proteins. Medicine and Science in Sports and Exercise. 49(10): 2016-2024, 2017.

Whitfield J, Paglialunga S, Smith BK, Mitoot PM, Simnett G, Robson HL, Jain SS, Herbst EAF, Desjardins EM, Dyck DJ, Spriet LL, Steinberg GR and Holloway GP. Ablating the Protein TBC1D1 Impairs Contraction-Induced Sarcolemmal Glucose Transporter 4 Re-distribution but not Insulin-Mediated Responses in Rats. Journal of Biological Chemistry. 292(40): 16653-16664, 2017.

2016

Chorner Z, Barbeau PA, Castellani L, Wright DC, and Holloway GP. Dietary α-Linolenic Acid Supplementation Alters Skeletal Muscle Plasma Membrane Lipid Composition, Sarcolemmal FAT/CD36 Abundance and Palmitate Transport. Am. J. Physiol. Regul. Integr. Comp. Physiol., 311(6): R1234-1242, 2017.

Herbst EA, Holloway GP. Exercise Increases Mitochondrial Glutamate Oxidation in the Mouse Cerebral Cortex. Appl. Physiol. Nutr. Metab. 41(7):799-801, 2016.

Matravadia S, Zabielski P, Chabowski A, Mutch DM, and Holloway GP. LA and ALA Prevent Glucose Intolerance in Obese Male Rats without Reducing Reactive Lipid Content, but Cause Tissue-Specific Changes in Fatty Acid Composition. Am. J. Physiol. Regul. Integr. Comp. Physiol. 310(7):R619-30, 2016.

Miotto PM, Holloway GP. In the Absence of Phosphate Shuttling, Exercise Reveals the In-Vivo Importance of Creatine-Independent Mitochondrial ADP Transport. Biochem. J. 473(18): 2831-43, 2016.

Miotto PM, Frendo-Cumbo S, Sacco SM, Wright DC, Ward WE, and Holloway GP. Combined High-Fat-Resveratrol Diet and RIP140 Knockout Mice Reveal A Novel Relationship Between Elevated Bone Mitochondrial Content and Compromised Bone Microarchitecture, Bone Mineral Mass, and Bone Strength in the Tibia. Mol. Nutr. Food Res. 60(9): 1994-2007, 2016.

Snook LA, Wright DC, and Holloway GP. Postprandial Control of Fatty Acid Transport Proteins' Subcellular Location is Not Dependent on Insulin. FEBS Lett. 590(16): 2661-70, 2016.

Whitfield J, Ludzki A, Heigenhauser GJ, Senden JM, Verdijk LB, van Loon LJ, Spriet LL, and Holloway GP. Beetroot Juice Supplementation Reduces Whole Body Oxygen Consumption but Does Not Improve Indices of Mitochondrial Efficiency in Human Skeletal Muscle. J. Physiol. 594(2):421-35, 2016.

2015

Bonen A, Jain SS, Snook LA, Han XX, Yoshida Y, Buddo KH, Lally JS, Pask ED, Paglialunga S, Beaudoin MS, Glatz JF, Luiken JJ, Harasim E, Wright DC, Chabowski A, and Holloway GP. Extremely Rapid Increase in Fatty Acid Transport and Intramyocellular Lipid Accumulation but Markedly Delayed Insulin Resistance After High Fat Feeding in Rats. Diabetologia. 58(10): 2381-91, 2015.

Herbst EA, Holloway GP. Exercise Training Normalizes Mitochondrial Respiratory Capacity Within the Striatum of the R6/1 Model of Huntington's Disease. Neuroscience. 303: 515-23, 2015.

Herbst EA, Holloway GP. Permeabilization of Brain Tissue in situ Enables Multiregion Analysis of Mitochondrial Function in a Single Mouse Brain. Journal of Physiology. 593(4): 787-801, 2015.

Herbst EA, Roussakis C, Matravadia S and Holloway GP. Chronic Treadmill Running Does Not Enhance Mitochondrial Oxidative Capacity in the Cortex or Striatum. Metabolism. 64(11): 1419-25, 2015.

Herbst EA, Bonen A and Holloway GP. Changes in Nuclear Receptor Co-Repressor RIP₁₄₀ do Not Influence Mitochondrial Content in the Cortex. Applied Physiology, Nutrition and Metabolism. 40 (10): 1086-8, 2015.

Ludzki A, Paglialunga S, Smith BK, Herbst EA, Allison MK, Heigenhauser GJ, Neufer PD, and Holloway GP. Rapid Repression of ADP Transport by Palmitoyl-CoA is Attenuated by Exercise Training in Humans: A Potential Mechanism to Decrease Oxidative Stress and Improve Skeletal Muscle Insulin Signaling. Diabetes. 64(8): 2769-79, 2015.

Monaco C, Whitfield J, Jain SS, Spriet LL, Bonen A, and Holloway GP. Activation of AMPKα2 is Not Required for Mitochondrial FAT/CD36 Accumulation During Exercise. PLoS One. 10(5):e0126122. 2015.

Paglialunga S, Ludzki A, Root-McCaig J, and Holloway GP. In Adipose Tissue, Increased Mitochondrial Emission of Reactive Oxygen Species is Important for Short-Term High-Fat Diet-Induced Insulin Resistance in Mice. Diabetologia. 58(5):1071-80, 2015.

Snook LA, Nelson EM, Dyck DJ, Wright DC, and Holloway GP. Glucose-Dependent Insulinotropic Polypeptide Directly Induces Glucose Transport in Rat Skeletal Muscle. Am. J. Physiol. Regul. Integr. Comp. Physiol. 309(3): R295-303, 2015.

2014

Beaudoin MS, Perry CG, Arkell AM, Chabowski A, Simpson JA, Wright DC and Holloway GP. Impairments in Mitochondrial Palmitoyl-CoA Respiratory Kinetics that Precede Development of Diabetic Cardiomyopathy are Prevented by Resveratrol in ZDF Rats. Journal of Physiology, 592(Pt 12): 2519-33, 2014.

Herbst EA, Paglialunga S, Gerling C, Whitfield J, Mukai K, Chabowski A, Heigenhauser GJ, Spriet LL and Holloway GP. Omega-3 Supplementation Alters Mitochondrial Membrane Composition and Respiration Kinetics in Human Skeletal Muscle. Journal of Physiology, 592(Pt 6): 1341-52, 2014.

Holloway GP, Han XX, Jain SS, Bonen A and Chabowski A. Chronic Muscle Stimulation Improves Insulin Sensitivity while Increasing Subcellular Lipid Droplets and Reducing Selected Diacylglycerol and Ceramide Species in Obese Zucker Rats. Diabetologia, 57(4): 832-40, 2014

Jain SS, Paglialunga S, Vigna C., Ludzki A, Herbst E. A., Lally J. S., Schrauwen P., Hoeks J., Tupling A. R., Bonen A and Holloway GP. High-Fat Diet-Induced Mitochondrial Biogenesis is Regulated by Mitochondrial Derived Reactive Oxygen Species Activation of CaMKII. Diabetes, 63(6):1907-13, 2014.

Matravadia S, Herbst EA, Jain SS, Mutch DM and Holloway GP. Linoleic and α-Linolenic Acid both Prevent Insulin Resistance but have Divergent Impacts on Skeletal Muscle Mitochondrial Bioenergetics in Obese Zucker Rats. Am. J. Physiol. Regul. Integr. Comp. Physiol., 307 (1): E102-14, 2014

Smith BK, Perry CG, Herbst EA, Ritchie IR, Beaudoin MS, Smith JC, Neufer PD, Wright DC, Holloway GP. Submaximal ADP-Stimulated Respiration is Impaired in ZDF Rats and Recovered by Resveratrol. J. Physiol. 2013; 591 (Pt 23):6089-101.

Matravadia S, Martino VB, Sinclair D, Mutch DM, Holloway GP. Exercise Training Increases the Expression and Nuclear Localization of mRNA Destabilizing Proteins in Skeletal Muscle. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2013; 305(7):R822-31.

Lally LS, Herbst EA, Matravadia S, Maher AC, Perry CG, Ventura-Clapeir R, Holloway GP. Over-Expressing Mitofusin-2 in Healthy Mature Mammalian Skeletal Muscle does Not Alter Mitochondrial Bioenergetics. PLoS One. 2013; 8(1):e55660.

Smith BK, Mukai K, Lally JS, Maher AC, Gurd BJ, Heigenhauser GJ, Spriet LL, Holloway GP. AMP-Activated Protein Kinase is Required for Exercise-Induced Peroxisome Proliferator-Activated Receptor Co-Activator 1 Translocation to Subsarcolemmal Mitochondria in Skeletal Muscle. J. Physiol. 2013; 591(Pt 6):1551-61.

Smith BK, Perry CG, Koves TR, Wright DC, Smith JC, Neufer PD, Muoio DM, Holloway GP. Identification of a Novel Malonyl-CoA IC(50) for CPT-1: Implications for Predicting in vivo Fatty Acid Oxidations Rates. Biochem. Journal. 2012; 448(1):13-20.

Lally JS, Snook LA, Han XX, Chabowski A, Bonen A, Holloway GP. Subcellular Lipid Droplet Distribution in Red and White Muscles in the Obese Zucker Rat. Diabetologia. 2012; 55(2):479-88.

Smith BK, Jain SS, Rimbaud S, Dam A, Quadrilatero J, Ventura-Clapier R, Bonen A, Holloway GP. FAT/CD36 is Located on the Outer Mitochondrial Membrane, Upstream of Long-Chain Acyl-CoA Synthetase, and Regulates Palmitate Oxidation. Biochem. Journal. 2011; 437(1):125-34.

• HK*4600 Applied Human Kinetics II
• HHNS*6130 Graduate Course In Advanced Skeletal Muscle Metabolism

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