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Review
. 2019 Aug 1;127(2):277-305.
doi: 10.1152/japplphysiol.00669.2018. Epub 2019 Feb 7.

The historical context and scientific legacy of John O. Holloszy

James M Hagberg  1 , Edward F Coyle  2 , Kenneth M Baldwin  3 , Gregory D Cartee  4 , Luigi Fontana  5 , Michael J Joyner  6 , John P Kirwan  7 , Douglas R Seals  8 , Edward P Weiss  9
Affiliations
Review

The historical context and scientific legacy of John O. Holloszy

James M Hagberg et al. J Appl Physiol (1985). .

Abstract

John O. Holloszy, as perhaps the world's preeminent exercise biochemist/physiologist, published >400 papers over his 50+ year career, and they have been cited >41,000 times. In 1965 Holloszy showed for the first time that exercise training in rodents resulted in a doubling of skeletal muscle mitochondria, ushering in a very active era of skeletal muscle plasticity research. He subsequently went on to describe the consequences of and the mechanisms underlying these adaptations. Holloszy was first to show that muscle contractions increase muscle glucose transport independent of insulin, and he studied the mechanisms underlying this response throughout his career. He published important papers assessing the impact of training on glucose and insulin metabolism in healthy and diseased humans. Holloszy was at the forefront of rodent studies of caloric restriction and longevity in the 1980s, following these studies with important cross-sectional and longitudinal caloric restriction studies in humans. Holloszy was influential in the discipline of cardiovascular physiology, showing that older healthy and diseased populations could still elicit beneficial cardiovascular adaptations with exercise training. Holloszy and his group made important contributions to exercise physiology on the effects of training on numerous metabolic, hormonal, and cardiovascular adaptations. Holloszy's outstanding productivity was made possible by his mentoring of ~100 postdoctoral fellows and substantial NIH grant funding over his entire career. Many of these fellows have also played critical roles in the exercise physiology/biochemistry discipline. Thus it is clear that exercise biochemistry and physiology will be influenced by John Holloszy for numerous years to come.

Keywords: aging; exercise; glucose; skeletal muscle; type 2 diabetes.

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Conflict of interest statement

All authors acknowledge that they underwent previous research training under the direction of Dr. John O. Holloszy.

Figures

Fig. 1.
Fig. 1.
Reprint cover sheet from Holloszy’s original 1967 article in the Journal of Biological Chemistry on the adaptations of rodent skeletal muscle to exercise training (J Biol Chem 242: 2278–2282, 1967). [Reproduced from Holloszy (78) with permission from the American Society for Biochemistry and Molecular Biology.]
Fig. 2.
Fig. 2.
Relationship of permeability to the frequency of stimulation in isolated frog muscles. Muscles of winter frogs were stimulated at 19° at various frequencies, and the plateau of permeability attained after 2 h is presented. Each point indicates the mean of 4 muscles, and vertical bars represent twice the SE. [Reproduced from Holloszy and Narahara (85) with permission from the American Society for Biochemistry and Molecular Biology.]
Fig. 3.
Fig. 3.
Effect of exercise on insulin sensitivity of glucose transport and cell surface GLUT-4 levels in rat epitrochlearis muscle. Rats were exercised by swimming for 2 h. Epitrochlearis muscles were incubated in vivo for 3 h and then were further incubated with the indicated concentration of insulin before measurement of 3-MG transport or cell surface GLUT-4 content. Data are means ± SE for n = 5 muscles/group (3-MG transport) or 10 (GLUT-4 concentrations). *P < 0.01, **P < 0.001 for exercised vs. sedentary. [Reproduced from Hansen et al. (66) with permission.]
Fig. 4.
Fig. 4.
Effect of stopping exercise for 10 days followed by one bout of usual exercise on plasma insulin responses to an oral glucose tolerance test (OGTT) in young trained men and women. Points are means SE for 8 subjects. *Trained vs. No exercise for 10 days, P < 0.05. †One bout of exercise vs. No exercise for 10 days P < 0.05. [Reproduced from Heath et al. (69) with permission.]
Fig. 5.
Fig. 5.
Plasma glucose (top panel) and insulin responses (bottom panel) to an oral glucose tolerance test (OGTT) in 5 type 2 diabetes patients before and after a 12-mo intense exercise training intervention. *P < 0.01. [Reproduced from Holloszy et al. (87) with permission from John Wiley. Copyright 2009 John Wiley & Sons.]
Fig. 6.
Fig. 6.
Plasma glucose (top panel) and insulin responses (bottom panel) to an oral glucose tolerance test (OGTT) in 8 individuals with impaired glucose tolerance before and after a 12-mo intense exercise training intervention. *P < 0.01. [Reproduced from Holloszy et al. (87) with permission from John Wiley. Copyright 2009 John Wiley & Sons.]
Fig. 7.
Fig. 7.
Effects of a 7-day exercise training program on insulin sensitivity and insulin responsiveness. GDR, glucose disposal rate. [Reproduced with Kirwan et al. (110) with permission.]
Fig. 8.
Fig. 8.
Plasma insulin responses during a hyperglycemic clamp and a 30-min recovery period, divided to show the early and late phases. The bottom panels represent the incremental insulin area above baseline. Mean ± SE are presented in the bar graphs. *Different from young (P < 0.05). ND/IGT, nondiagnostic/impaired glucose tolerance. [Reproduced from Bourey et al. (11) with permission from Oxford University Press. Copyright 1993 Oxford University Press.]
Fig. 9.
Fig. 9.
Survival curves of control rats compared with those who underwent cold exposure to assess the “rate of living” theory of aging. [Reproduced from Holloszy and Smith (90) with permission.]
Fig. 10.
Fig. 10.
Survival curves for four groups: group A: runners; group B: sedentary controls; group C: food-restricted runners; and group D: food-restricted sedentary controls. Survival curve for sedentary control rats in group B is significantly different from that of runners in group A (P < 0.02), food-restricted runners in group C (P < 0.0001), and food-restricted sedentary rats in group D (P < 0.0001). Survival curve for runners in group A is significantly different from that of food-restricted runners in group C (P < 0.01) and food-restricted sedentary rats in group D (P < 0.01). [Reproduced from Holloszy (80) with permission.]
Fig. 11.
Fig. 11.
Long-term effects of caloric restriction and protein restriction on serum IGF-1 concentration (A) and the ratio of IGF-1 to IGFBP-3 concentrations (B). Data from the cross-sectional comparison of individuals who were habitually consuming a low-protein diet, a low-calorie diet, or a typical Western diet. Data are means SE. *P ≤ 0.01 vs. the low-calorie group. †P ≤ 0.01 vs. the Western diet group. [Reproduced from Fontana et al. (50) under Creative Commons Attribution License 4.0.]
Fig. 12.
Fig. 12.
Doppler mitral valve inflow patterns for a typical young healthy individual on a Western diet (WD), an older individual on a Western diet (WD), and an older caloric-restricted (CR) individual. [Reproduced from Meyer et al. (125) with permission from Elsevier Inc. Copyright The American College of Cardiology Foundation.]
Fig. 13.
Fig. 13.
Oral glucose tolerance test (OGTT) glucose and insulin responses for individuals with initial abnormal glucose tolerance in the placebo and DHEA supplementation groups. The reduction in glucose area under the curve (AUC) in the DHEA group (C) was significantly greater than that for the placebo group (A; P = 0.03). Changes in the insulin AUC did not differ between groups (B and D; P = 0.52). Improvements in glucose AUC were maintained in a subset of DHEA group participants who completed a 2nd yr of DHEA supplementation (E; P < 0.05 for baseline vs. DHEA). *P < 0.05 for baseline versus DHEA. [Reproduced from Weiss et al. (184) under Creative Commons Attribution License 3.0. Copyright Weiss et al. (184).]
Fig. 14.
Fig. 14.
Decline in V̇o2max with age in groups of sedentary and exercise-training men and the masters athletes. Individual data points are average V̇o2max values for groups of men of different ages from 13 reports in the literature and for young athletes, masters athletes, lean untrained, and overweight untrained men in Heath et al. (70). [Reproduced from Heath et al. (70) with permission.]
Fig. 15.
Fig. 15.
The relationship between the extent of ST-segment depression and the double product at different intensities of exercise before (solid circle and line) and after (open circle, dashed line) 12 mo of exercise training in coronary artery disease (CAD) patients. SBP, systolic blood pressure; HR, heart rate. Values are means ± SD. *Before training vs. after training, P < 0.02. [Reproduced from Ehsani et al. (42) with permission. Copyright American Heart Association.]
Fig. 16.
Fig. 16.
Increases in subjects’ average V̇o2max during the 10-wk intensive Hickson training program. [Reproduced from Hickson et al. (75) with permission.]
Fig. 17.
Fig. 17.
Semilogarithmic plots of the increase in V̇o2max during two training periods utilizing the Hickson training protocol. Values plotted are the differences between the new, higher steady state (V̇o2ss) and the values at given times during training (V̇o2t). [Reproduced from Hickson et al. (76) with permission from Wolters Kluwer Health, Inc. Copyright American College of Sports Medicine.]
Fig. 18.
Fig. 18.
Sequences of detraining changes in citrate synthase (cit syn) and lactate dehydrogenase (LDH) in type I and type II vastus lateralis fibers from cyclist A (Holloszy). Fiber types are indicated by I and II. Each point is average ± SE for 6–23 fibers in the case of LDH and 6–16 fibers (chosen from the same groups) in the case of citrate synthase. Control indicates average for vastus lateralis fibers from both controls. Activities are in mol·kg dry wt−1·h−1 at 20°C. Note scale for citrate synthase is 0–8 instead of 0–80. [Reproduced from Chi et al. (16) with permission.]
Fig. 19.
Fig. 19.
The three generations of the John O. Holloszy scientific family tree. Permission to use the picture of Dr. John Holloszy is provided from the Washington University School of Medicine Division of Geriatrics and Nutritional Science. [Photo in middle used with permission. Copyright Whitehall Photography (www.whitehallphotography.com).]
See this image and copyright information in PMC

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References

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