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Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence?
Open accessAbstract
BACKGROUND: Individuals differ in the response to regular exercise. Whether there are people who experience adverse changes in cardiovascular and diabetes risk factors has never been addressed. METHODOLOGY/PRINCIPAL FINDINGS: An adverse response is defined as an exercise-induced change that worsens a risk factor beyond measurement error and expected day-to-day variation. Sixty subjects were measured three times over a period of three weeks, and variation in resting systolic blood pressure (SBP) and in fasting plasma HDL-cholesterol (HDL-C), triglycerides (TG), and insulin (FI) was quantified. The technical error (TE) defined as the within-subject standard deviation derived from these measurements was computed. An adverse response for a given risk factor was defined as a change that was at least two TEs away from no change but in an adverse direction. Thus an adverse response was recorded if an increase reached 10 mm Hg or more for SBP, 0.42 mmol/L or more for TG, or 24 pmol/L or more for FI or if a decrease reached 0.12 mmol/L or more for HDL-C. Completers from six exercise studies were used in the present analysis: Whites (N = 473) and Blacks (N = 250) from the HERITAGE Family Study; Whites and Blacks from DREW (N = 326), from INFLAME (N = 70), and from STRRIDE (N = 303); and Whites from a University of Maryland cohort (N = 160) and from a University of Jyvaskyla study (N = 105), for a total of 1,687 men and women. Using the above definitions, 126 subjects (8.4%) had an adverse change in FI. Numbers of adverse responders reached 12.2% for SBP, 10.4% for TG, and 13.3% for HDL-C. About 7% of participants experienced adverse responses in two or more risk factors. CONCLUSIONS/SIGNIFICANCE: Adverse responses to regular exercise in cardiovascular and diabetes risk factors occur. Identifying the predictors of such unwarranted responses and how to prevent them will provide the foundation for personalized exercise prescription.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
Adverse metabolic responses to regular exercise—worsening of systolic blood pressure, HDL-cholesterol, triglycerides, or fasting insulin beyond measurement error—occur in a nontrivial minority of adults across six exercise studies. The paper estimates prevalences of roughly 8%–13% per risk factor and about 7% for two or more risk factors.
Key findings
- Across six exercise studies (maximum N = 1,687), adverse responder prevalence was 8.3% for fasting insulin (abstract states 8.4%), 13.3% for HDL-C, 10.3% for triglycerides, and 12.2% for systolic blood pressure.
- In HERITAGE, 6%–9% of Blacks and Whites experienced adverse responses for each of the four risk factors, with no substantive differences between ethnic groups.
- About 7% of participants experienced adverse responses in two or more risk factors; Table 8 reports 6% with exactly two and 0.8% with three or four.
- Adverse response traits appeared independent of cardiorespiratory fitness improvement: only 2 of 56 tested differences in VO2max gain between adverse and non-adverse responders reached p ≤ 0.05, far from a Bonferroni-adjusted p = 0.0009. DREW showed no substantive differences in adverse response prevalence across 4, 8, or 12 kcal/kg/week exercise doses.
Methods
- Secondary analysis of completers from six exercise intervention studies: HERITAGE (473 Whites, 250 Blacks), DREW (326), INFLAME (70), STRRIDE (303), MARYLAND (160), and JYVASKYLA (105), for a maximum of 1,687 men and women.
- Adverse response was defined as an exercise-induced change at least 2× the technical error (TE) in an adverse direction: increase ≥10 mm Hg for systolic BP, ≥0.42 mmol/L for triglycerides, ≥24 pmol/L for fasting insulin, or decrease ≤0.12 mmol/L for HDL-C. TE was derived from 60 subjects measured three times over 3 weeks, except fasting insulin, for which assays were performed twice and TE was estimated using other HERITAGE data plus literature.
- Analyses included prevalence tabulations, paired t tests for within-cohort mean changes, general linear models comparing VO2max gains between adverse and non-adverse responders with age, sex, and baseline VO2max as covariates, and a DREW dose comparison.
Limitations
- The paper states that the causes of adverse responses are unknown, that exercise-drug interactions cannot be directly tested with available data, and that it is unknown whether some adverse responders would revert with different exercise doses or modalities; findings also need extension to other risk factors such as LDL-cholesterol, inflammation markers, and adiposity traits.
- Evident from the text: this is a secondary analysis of completers from heterogeneous studies with differing protocols and health statuses, some trait data are unavailable (e.g., STRRIDE systolic BP is N/A), and the fasting insulin TE was not based on three repeated measurements but estimated from other data and literature.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Adverse responses to regular exercise in cardiovascular and diabetes risk factors occur.”
- Also stated in: § Discussion · plain
“Thus, some individuals experience ARs when exposed to regular exercise, but the causes of the phenomenon are unknown at this time.”
§ Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence? > Abstract > Conclusions/Significance
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Completers of the six exercise studies are representative of sedentary adults generally.
- Also stated in: § Discussion · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Numbers of adverse responders reached 12.2% for SBP, 10.4% for TG, and 13.3% for HDL-C.”
- Also stated in: § Results · plain
“Based on a maximum of 1687 subjects, the prevalence of an AR reached 8.3% for the changes in FI, 13.3% for the changes in fasting HDL-C, 10.3% for TG, and 12.2% for resting SBP.”
§ Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence? > Abstract > Methodology/Principal Findings
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The technical error estimates derived from the HERITAGE ancillary study apply to the other five exercise studies.
- Rests on an assumption: The six exercise studies are sufficiently comparable to pool for estimating overall prevalence of adverse responses.
- Rests on an assumption: Attrition in the six studies did not bias the prevalence estimates of adverse responses.
- Also stated in: § Results · plain
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“All gains in VO2max are significant at p<0.05.”
§ Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence? > Results
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Yet substantial numbers of subjects with or without medication in these cohorts experienced one or more ARs.”
§ Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence? > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Medication use reported in the cohorts is accurate and does not confound the comparison of adverse response prevalence.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Only a small minority of participants (<1%) exhibited ARs for three or more traits.”
§ Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence? > Results
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The six exercise studies are sufficiently comparable to pool for estimating overall prevalence of adverse responses.
- Rests on an assumption: Attrition in the six studies did not bias the prevalence estimates of adverse responses.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The prevalence of ARs appears to be similar at low and high doses of exercise.”
- Also stated in: § Results · plain
“No substantive differences were observed in the prevalence of ARs among the three levels of exercise energy expenditure, which ranged from 4 to 12 kcal/kg of body weight per week.”
§ Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence? > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Results · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Numbers of adverse responders reached 12.2% for SBP, 10.4% for TG, and 13.3% for HDL-C.”
- Also stated in: § Results · plain
“Based on a maximum of 1687 subjects, the prevalence of an AR reached 8.3% for the changes in FI, 13.3% for the changes in fasting HDL-C, 10.3% for TG, and 12.2% for resting SBP.”
§ Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence? > Abstract > Methodology/Principal Findings
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The technical error estimates derived from the HERITAGE ancillary study apply to the other five exercise studies.
- Rests on an assumption: The six exercise studies are sufficiently comparable to pool for estimating overall prevalence of adverse responses.
- Rests on an assumption: Attrition in the six studies did not bias the prevalence estimates of adverse responses.
- Also stated in: § Results · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Numbers of adverse responders reached 12.2% for SBP, 10.4% for TG, and 13.3% for HDL-C.”
- Also stated in: § Results · plain
“Based on a maximum of 1687 subjects, the prevalence of an AR reached 8.3% for the changes in FI, 13.3% for the changes in fasting HDL-C, 10.3% for TG, and 12.2% for resting SBP.”
§ Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence? > Abstract > Methodology/Principal Findings
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The technical error estimates derived from the HERITAGE ancillary study apply to the other five exercise studies.
- Rests on an assumption: The six exercise studies are sufficiently comparable to pool for estimating overall prevalence of adverse responses.
- Rests on an assumption: Attrition in the six studies did not bias the prevalence estimates of adverse responses.
- Also stated in: § Results · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The prevalence of ARs for select risk factors varied from 8.3% for the exercise training-induced changes in FI to 13.3% for the changes in HDL-C, with about 7% of participants experiencing adverse changes in two or more risk factors.”
§ Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence? > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Even though the presence of ARs was first detected among completers in Blacks and Whites of the HERITAGE Family Study, in which subjects were confirmed to be sedentary at baseline, with a rather healthy profile, the phenomenon was confirmed in five other exercise intervention studies.”
§ Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence? > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 6
- The quote only partly states this claim. 1
- Probably not a substantial claim. 1
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although HERITAGE subjects were apparently healthy and not taking medication for blood pressure, glucose, or lipid anomalies and were exposed to the same exercise program, 6% to 9% of Blacks and Whites experienced ARs for each of the four risk factors, with no substantive differences between the two ethnic groups.”
§ Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence? > Results
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Using the above definitions, 126 subjects (8.4%) had an adverse change in FI.”
- Also stated in: § Results · plain
“Based on a maximum of 1687 subjects, the prevalence of an AR reached 8.3% for the changes in FI, 13.3% for the changes in fasting HDL-C, 10.3% for TG, and 12.2% for resting SBP.”
§ Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence? > Abstract > Methodology/Principal Findings
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe quote only partly states this claim.
- Rests on an assumption: The technical error estimates derived from the HERITAGE ancillary study apply to the other five exercise studies.
- Rests on an assumption: The six exercise studies are sufficiently comparable to pool for estimating overall prevalence of adverse responses.
- Rests on an assumption: Attrition in the six studies did not bias the prevalence estimates of adverse responses.
- Also stated in: § Results · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The mean changes induced by the exercise programs were generally in the expected direction (i.e., decreases in FI, TG, and SBP and increases in HDL-C). There were, however, some statistically nonsignificant exceptions to these general trends.”
§ Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence? > Results
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The four risk factors (systolic blood pressure, fasting insulin, HDL-cholesterol, and triglycerides) are valid indicators of cardiovascular and diabetes risk.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, we did not find any evidence for differences in the prevalence of ARs between Blacks and Whites or between men and women.”
§ Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence? > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In the case of FI, the assays were performed only twice, and we used other HERITAGE data plus observations from the literature to develop an estimate of TE for FI (Information S1).”
§ Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence? > Methods > Definition of adverse responses
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“There are strong indications from a baseline skeletal muscle gene expression profile and from a genome-wide association study performed on the Whites of HERITAGE that the genetic component of a response trait can be defined in terms of RNA abundance observed in the sedentary state or by specific genomic variants [31], [32], [33].”
§ Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence? > Discussion
What the sources say
- Not checked — no full text of the sourcecites [31] C Bouchard, 2011, Genomic predictors of the maximal O uptake response to standardized exercise training programs., J Appl Physiol source
- Not checked — no full text of the sourcecites [32] JA Timmons, 2010, Using molecular classification to predict gains in maximal aerobic capacity following endurance exercise training in humans., J Appl Physiol source
- Not checked — no full text of the sourcecites [33] T Rankinen, 2012, The heritability of submaximal exercise heart rate response to exercise training is accounted for by nine SNPs., J Appl Physiol source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“In fact, the heritability of the changes induced by the exercise program reached about 30% for plasma HDL-C and TG [26] and about 20% to 25% for indicators of insulin metabolism and resting SBP [29], [30].”
§ Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence? > Discussion
What the sources say
- Not checked — no full text of the sourcecites [26] T Rice, 2002, Familial aggregation of blood lipid response to exercise training in the health, risk factors, exercise training, and genetics (HERITAGE) Family Study., Circulation source
- Not checked — no full text of the sourcecites [29] P An, 2005, Genome-wide linkage scans for prediabetes phenotypes in response to 20 weeks of endurance exercise training in non-diabetic whites and blacks: the HERITAGE Family Study., Diabetologia source
- Not checked — no full text of the sourcecites [30] T Rice, 2002, Heritability of HR and BP response to exercise training in the HERITAGE Family Study., Med Sci Sports Exerc source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, ARs as defined herein for common cardiometabolic and diabetes risk factors are much more prevalent and become evident with exposure to regular exercise.”
§ Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence? > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper relies on this without support.
Completers of the six exercise studies are representative of sedentary adults generally.
“Approximately 7% of sedentary adults experienced ARs for at least two common cardiometabolic and diabetes risk factors following exposure to regular exercise.”
The paper relies on this without support.
The technical error estimates derived from the HERITAGE ancillary study apply to the other five exercise studies.
“An ancillary study designed to quantify TE for several biological traits was undertaken in HERITAGE.”
“These AR definitions are used in the remainder of this report.”
The paper relies on this without support.
The six exercise studies are sufficiently comparable to pool for estimating overall prevalence of adverse responses.
“Based on a maximum of 1687 subjects, the prevalence of an AR reached 8.3% for the changes in FI, 13.3% for the changes in fasting HDL-C, 10.3% for TG, and 12.2% for resting SBP.”
The paper relies on this without support.
Attrition in the six studies did not bias the prevalence estimates of adverse responses.
“Completers from six exercise studies were used in the present analysis”
The paper relies on this without support.
The four risk factors (systolic blood pressure, fasting insulin, HDL-cholesterol, and triglycerides) are valid indicators of cardiovascular and diabetes risk.
“with a focus on exercise-induced changes in resting systolic blood pressure (SBP), fasting insulin (FI), HDL-cholesterol (HDL-C), and triglycerides (TG).”
The paper relies on this without support.
Medication use reported in the cohorts is accurate and does not confound the comparison of adverse response prevalence.
“many subjects in DREW, INFLAME, MARYLAND, and STRRIDE were taking medications for high blood pressure, hyperglycemia, or dyslipoproteinemia. Yet substantial numbers of subjects with or without medication in these cohorts experienced one or more ARs.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“It has been previously suggested that for 20% to 25% of participants undertaking an exercise programme there is little to no favourable response (Timmons 2014), while a small percentage (5% to 10%) have adverse events (Bouchard 2012).”
From Physical activity and exercise for chronic pain in adults: an overview of Cochrane Reviews (2017) · cites this paper as Bouchard 2012
In the citing paper
“7–15% of individuals demonstrated an ‘adverse response’ regarding alterations in systolic blood pressure, as well as in fasting levels of HDL cholesterol, triglycerides and insulin25,26.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [26]
In the citing paper
“Moreover, in humans, metabolic non-response or even adverse responses to exercise have been described26.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [26]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Fasting-insulin adverse-response prevalence differs
MinorThe abstract reports 8.4% for fasting insulin, while the Results and Table 5 report 8.3% for the same 126 adverse responders.
“126 subjects (8.4%) had an adverse change in FI.”
“| Δ Fasting insulin | 55 | 36 | 12 | 17 | 4 | 2 | 126 | 8.3 |”
Triglyceride adverse-response prevalence differs
MinorThe abstract reports 10.4% for triglycerides, while the Results and Table 5 report 10.3%.
“Numbers of adverse responders reached 12.2% for SBP, 10.4% for TG, and 13.3% for HDL-C.”
“| Δ Triglycerides | 56 | 51 | 9 | 34 | 11 | 11 | 172 | 10.3 |”
Citations
Cites
Individual differences in response to regular physical activity
BOUCHARD, C., & RANKINEN, T. (2001) · Medicine and Science in Sports and Exercise · doi:10.1097/00005768-200106001-00013 · Cited by 939 · cited 1×
“This clear finding of the HERITAGE Family Study has been replicated [3,4,5,6].”
BackgroundSelf-citationBouchard, C., An, P., Rice, T., Skinner, J. S., Wilmore, J. H., Gagnon, J., Pérusse, L., Leon, A. S., & Rao, D. C. (1999) · Journal of Applied Physiology · doi:10.1152/jappl.1999.87.3.1003 · Cited by 875 · cited 1×
“Research based on HERITAGE has amply demonstrated that the response pattern to exercise training aggregates in families [25,26,27,28].”
BackgroundSelf-citationThe Incidence of Primary Cardiac Arrest during Vigorous Exercise
Siscovick, D. S., Weiss, N. S., Fletcher, R. H., & Lasky, T. (1984) · New England Journal of Medicine · doi:10.1056/nejm198410043111402 · Cited by 838 · cited 1×
“It is important to differentiate between ARs for risk factors for common chronic diseases, as referred to in the present study, from other more acute ARs such as cardiac events related to exertion during an exercise bout [20,21,22], sudden cardiac death during or immediately after exercise typically associated with a…”
BackgroundChurch, T. S., Earnest, C. P., Skinner, J. S., & Blair, S. N. (2007) · JAMA · doi:10.1001/jama.297.19.2081 · Cited by 756 · cited 2×
“This clear finding of the HERITAGE Family Study has been replicated [3,4,5,6].”
BackgroundMethodSelf-citationThe Human Gene Map for Performance and Health-Related Fitness Phenotypes
Rankinen, T., Bray, M. S., Hagberg, J. M., Përusse, L., Roth, S. M., Wolfarth, B., & Bouchard, C. (2006) · Medicine & Science in Sports & Exercise · doi:10.1249/01.mss.0000233789.01164.4f · Cited by 734
Self-citationCardiac arrest during long-distance running races
Kim, J. H., Malhotra, R., Chiampas, G., d'Hemecourt, P., Troyanos, C., Cianca, J., Smith, R. N., Wang, T. J., Roberts, W. O., Thompson, P. D., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1106468 · Cited by 597 · cited 1×
“It is important to differentiate between ARs for risk factors for common chronic diseases, as referred to in the present study, from other more acute ARs such as cardiac events related to exertion during an exercise bout [20,21,22], sudden cardiac death during or immediately after exercise typically associated with a…”
BackgroundGenomic predictors of the maximal O2 uptake response to standardized exercise training programs
Bouchard, C., Sarzynski, M. A., Rice, T. K., Kraus, W. E., Church, T. S., Sung, Y. J., Rao, D. C., & Rankinen, T. (2011) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00973.2010 · Cited by 422 · cited 1×
“There are strong indications from a baseline skeletal muscle gene expression profile and from a genome-wide association study performed on the Whites of HERITAGE that the genetic component of a response trait can be defined in terms of RNA abundance observed in the sedentary state or by specific genomic variants [31,3…”
BackgroundSelf-citationTimmons, J. A., Knudsen, S., Rankinen, T., Koch, L. G., Sarzynski, M., Jensen, T., Keller, P., Scheele, C., Vollaard, N. B. J., Nielsen, S., et al. (2010) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01295.2009 · Cited by 358 · cited 1×
“There are strong indications from a baseline skeletal muscle gene expression profile and from a genome-wide association study performed on the Whites of HERITAGE that the genetic component of a response trait can be defined in terms of RNA abundance observed in the sedentary state or by specific genomic variants [31,3…”
BackgroundSelf-citationEffects of Exercise Training on Glucose Homeostasis
Boulé, N. G., Weisnagel, S. J., Lakka, T. A., Tremblay, A., Bergman, R. N., Rankinen, T., Leon, A. S., Skinner, J. S., Wilmore, J. H., Rao, D. C., et al. (2005) · Diabetes Care · doi:10.2337/diacare.28.1.108 · Cited by 356 · cited 1×
“This clear finding of the HERITAGE Family Study has been replicated [3,4,5,6].”
BackgroundSelf-citationThe HERITAGE family study. Aims, design, and measurement protocol.
Bouchard, C., Leon, A. S., Rao, D. C., Skinner, J. S., Wilmore, J. H., & Gagnon, J. (1995) · PubMed · Cited by 331
Self-citationAims, design, and measurement protocol
BOUCHARD, C., LEON, A. S., RAO, D. C., SKINNER, J. S., WlLMORE, J. H., & GAGNON, J. (1995) · Medicine & Science in Sports & Exercise · doi:10.1249/00005768-199505000-00015 · Cited by 271 · cited 1×
“HERITAGE (Health, Risk Factors, Exercise Training And Genetics) Family Study The sample, study design, and exercise training protocol of HERITAGE have been described elsewhere [7].”
MethodSelf-citationBateman, L. A., Slentz, C. A., Willis, L. H., Shields, A. T., Piner, L. W., Bales, C. W., Houmard, J. A., & Kraus, W. E. (2011) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2011.04.037 · Cited by 246 · cited 1×
“Studies of a Targeted Risk Reduction Intervention through Defined Exercise (STRRIDE) STRRIDE (84% Whites) includes two complementary studies [10,11].”
BackgroundSelf-citationStudies of a targeted risk reduction intervention through defined exercise (STRRIDE)
Kraus, W. E., TORGAN, C. E., Duscha, B. D., Norris, J. M., Brown, S. A., Cobb, F. R., Bales, C. W., Annex, B. H., Samsa, G. P., Houmard, J. A., et al. (2001) · Medicine & Science in Sports & Exercise · doi:10.1097/00005768-200110000-00025 · Cited by 144 · cited 1×
“Studies of a Targeted Risk Reduction Intervention through Defined Exercise (STRRIDE) STRRIDE (84% Whites) includes two complementary studies [10,11].”
BackgroundSelf-citationIndividual responses to combined endurance and strength training in older adults.
KARAVIRTA, L., HÄKKINEN, K., KAUHANEN, A., ARIJA-BLÁZQUEZ, A., SILLANPÄÄ, E., RINKINEN, N., & HÄKKINEN, A. (2011) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0b013e3181f1bf0d · Cited by 139 · cited 1×
“University of Jyväskylä Study (JYVASKYLA) Healthy, sedentary 40- to 67-year-old men and women were recruited [13].”
MethodSelf-citationThe human gene map for performance and health-related fitness phenotypes: the 2001 update
Rankinen, T., Përusse, L., Rauramaa, R., Rivera, M. A., Wolfarth, B., & Bouchard, C. (2002) · Medicine & Science in Sports & Exercise · doi:10.1097/00005768-200208000-00001 · Cited by 119 · cited 1×
“It is important to differentiate between ARs for risk factors for common chronic diseases, as referred to in the present study, from other more acute ARs such as cardiac events related to exertion during an exercise bout [20,21,22], sudden cardiac death during or immediately after exercise typically associated with a…”
BackgroundSelf-citationVariability in the Response of HDL Cholesterol to Exercise Training in the HERITAGE Family Study
Leon, A. S., Gaskill, S. E., Rice, T., Bergeron, J., Gagnon, J., Rao, D. C., Skinner, J. S., Wilmore, J. H., & Bouchard, C. (2002) · International Journal of Sports Medicine · doi:10.1055/s-2002-19270 · Cited by 116 · cited 1×
“This clear finding of the HERITAGE Family Study has been replicated [3,4,5,6].”
BackgroundSelf-citationDose-Response to Exercise in Women Aged 45???75 yr (DREW): Design and Rationale
Morss, G. M., Jordan, A., Skinner, J. S., Dunn, A. L., Church, T. S., Earnest, C. P., Kampert, J. B., Jurča, R., & Blair, S. N. (2004) · Medicine & Science in Sports & Exercise · doi:10.1249/01.mss.0000113738.06267.e5 · Cited by 110
Self-citationReproducibility of maximal exercise test data in the HERITAGE Family Study
Skinner, J. S., WILMORE, K. M., Jaskólska, A., Jaskólski, A., Daw, E. W., Rice, T., Gagnon, J., Leon, A. S., Wilmore, J. H., Rao, D. C., et al. (1999) · Medicine & Science in Sports & Exercise · doi:10.1097/00005768-199911000-00020 · Cited by 99 · cited 1×
“Sixty subjects were measured three times (except for FI) over a period of 3 weeks for each trait [15,16,17,18,19].”
BackgroundSelf-citationSelected body measurements of children 6-11 years.
Malina, R., Hamill, P., & Lemeshow, S. (1973) · Vital and health statistics. Series 11, Data from the National Health Survey · doi:10.1111/j.1753-4887.1973.tb05072.x · Cited by 87
Heritability of HR and BP response to exercise training in the HERITAGE Family Study
RICE, T., AN, P., GAGNON, J., LEON, A. S., SKINNER, J. S., WILMORE, J. H., BOUCHARD, C., & RAO, D. C. (2002) · Medicine & Science in Sports & Exercise · doi:10.1097/00005768-200206000-00011 · Cited by 83 · cited 8×
“Numbers of adverse responders reached 12.2% for SBP, 10.4% for TG, and 13.3% for HDL-C.”
BackgroundInfluentialSelf-citationRice, T., Després, J.-P., Pérusse, L., Hong, Y., Province, M. A., Bergeron, J., Gagnon, J., Leon, A. S., Skinner, J. S., Wilmore, J. H., et al. (2002) · Circulation · doi:10.1161/01.cir.0000014969.85364.9f · Cited by 65
Self-citationReproducibility of anthropometric and body composition measurements: the HERITAGE Family Study
Wilmore, J., Stanforth, P., Domenick, M., Gagnon, J., Daw, E., Leon, A., Rao, D., Skinner, J., & Bouchard, C. (1997) · International Journal of Obesity · doi:10.1038/sj.ijo.0800404 · Cited by 61
Self-citationWILMORE, J. H., STANFORTH, P. R., TURLEY, K. R., GAGNON, J., DAW, E. W., LEON, A. S., RAO, D. C., SKINNER, J. S., & BOUCHARD, C. (1998) · Medicine & Science in Sports & Exercise · doi:10.1097/00005768-199802000-00014 · Cited by 57 · cited 1×
“Sixty subjects were measured three times (except for FI) over a period of 3 weeks for each trait [15,16,17,18,19].”
BackgroundSelf-citationAn, P., Teran-Garcia, M., Rice, T., Rankinen, T., Weisnagel, S. J., Bergman, R. N., Boston, R. C., Mandel, S., Stefanovski, D., Leon, A. S., et al. (2005) · Diabetologia · doi:10.1007/s00125-005-1769-4 · Cited by 54 · cited 8×
“Numbers of adverse responders reached 12.2% for SBP, 10.4% for TG, and 13.3% for HDL-C.”
BackgroundInfluentialSelf-citationThe HERITAGE Family Study: Quality assurance and quality control.
Gagnon, J. (1996) · Annals of Epidemiology · doi:10.1016/s1047-2797(96)00068-3 · Cited by 52 · cited 1×
“Sixty subjects were measured three times (except for FI) over a period of 3 weeks for each trait [15,16,17,18,19].”
BackgroundDesprés, J., Gagnon, J., Bergeron, J., Couillard, C., Leon, A. S., Rao, D. C., Skinner, J. S., Wilmore, J. H., & Bouchard, C. (1999) · Clinical Biochemistry · doi:10.1016/s0009-9120(98)00106-4 · Cited by 48
Self-citationRankinen, T., Sung, Y. J., Sarzynski, M. A., Rice, T. K., Rao, D. C., & Bouchard, C. (2012) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01287.2011 · Cited by 45
Self-citationWilund, K. R., Colvin, P. L., Phares, D. A., Goldberg, A. P., & Hagberg, J. M. (2002) · Metabolism · doi:10.1053/meta.2002.33356 · Cited by 31 · cited 1×
“University of Maryland Gene Exercise Research Study (MARYLAND) Briefly, 160 men and women (100% Whites) ages 50 to 75 years who were sedentary, nondiabetic, and nonsmoking, with no prior history of cardiovascular disease but with one National Cholesterol Education Program lipid abnormality or blood pressure in the pre…”
BackgroundSelf-citationSelected body measurements of children 6-11 years.
(1973) · PubMed · Cited by 30
Athletes, athletics, and sudden cardiac death
THOMPSON, P. D. (1993) · Medicine & Science in Sports & Exercise · doi:10.1249/00005768-199309000-00001 · Cited by 24 · cited 1×
“It is important to differentiate between ARs for risk factors for common chronic diseases, as referred to in the present study, from other more acute ARs such as cardiac events related to exertion during an exercise bout [20,21,22], sudden cardiac death during or immediately after exercise typically associated with a…”
BackgroundExercise and Sudden Cardiac Death
Thompson, P. D., & Mitchell, J. H. (1984) · New England Journal of Medicine · doi:10.1056/nejm198410043111410 · Cited by 23 · cited 1×
“It is important to differentiate between ARs for risk factors for common chronic diseases, as referred to in the present study, from other more acute ARs such as cardiac events related to exertion during an exercise bout [20,21,22], sudden cardiac death during or immediately after exercise typically associated with a…”
BackgroundInflammation and exercise (INFLAME): Study rationale, design, and methods
Thompson, A. M., Mikus, C. R., Rodarte, R. Q., Distefano, B., Priest, E. L., Sinclair, E., Earnest, C. P., Blair, S. N., & Church, T. S. (2007) · Contemporary Clinical Trials · doi:10.1016/j.cct.2007.09.009 · Cited by 20 · cited 1×
“0 mg/L) were randomized to an endurance exercise or a control group [9].”
MethodSelf-citation(2000) · PubMed · Cited by 18
Self-citationFamiliality of triglyceride and LPL response to exercise training: the HERITAGE Study
Hong, Y., Rice, T., & Gagnon, J. (2000) · Medicine & Science in Sports & Exercise · doi:10.1097/00005768-200008000-00012 · Cited by 13 · cited 1×
“Research based on HERITAGE has amply demonstrated that the response pattern to exercise training aggregates in families [25,26,27,28].”
Background
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Exercise Metabolism and the Molecular Regulation of Skeletal Muscle Adaptation
Egan, B., & Zierath, J. R. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2012.12.012 · Cited by 2,084
“…participants engage in carefully controlled exercise training regimens, the nature of the training response is remarkably heterogeneous, allowing the classification of non-, low, and high responders (Bouchard et al., 1999; Hubal et al., 2005), and even adverse responders (Bouchard et al., 2012).”
BackgroundInternational exercise recommendations in older adults (ICFSR): Expert consensus guidelines
Izquierdo, M., Merchant, R. A., Morley, J. E., Anker, S. D., Aprahamian, I., Arai, H., Aubertin-Leheudre, M., Bernabei, R., Cadore, E. L., Cesari, M., et al. (2021) · The Journal of nutrition, health and aging · doi:10.1007/s12603-021-1665-8 · Cited by 1,247
Physical activity and exercise for chronic pain in adults: an overview of Cochrane Reviews
Geneen, L. J., Moore, R. A., Clarke, C., Martin, D., Colvin, L. A., & Smith, B. H. (2017) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd011279.pub3 · Cited by 1,222
Exerkines in health, resilience and disease
Chow, L. S., Gerszten, R. E., Taylor, J. M., Pedersen, B. K., van Praag, H., Trappe, S., Febbraio, M. A., Galis, Z. S., Gao, Y., Haus, J. M., et al. (2022) · Nature Reviews Endocrinology · doi:10.1038/s41574-022-00641-2 · Cited by 927
Physical activity and exercise for chronic pain in adults: an overview of Cochrane Reviews
Geneen, L. J., Moore, R. A., Clarke, C., Martin, D., Colvin, L. A., & Smith, B. H. (2017) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd011279.pub2 · Cited by 719
Metadata
- Authors
- Bouchard, C., Blair, S. N., Church, T. S., Earnest, C. P., Hagberg, J. M., Häkkinen, K., Jenkins, N. T., Karavirta, L., Kraus, W. E., Leon, A. S., Rao, D. C., Sarzynski, M. A., Skinner, J. S., Slentz, C. A., & Rankinen, T.
- Affiliations
- Pennington Biomedical Research Center (US)
- University of South Carolina (US)
- University of Maryland, College Park (US)
- University of Jyväskylä (FI)
- Duke Medical Center (US)
- University of Minnesota (US)
- Washington University in St. Louis (US)
- Indiana University Bloomington (US)
- Corresponding author
- Bouchard, Claude
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-05-30
- Volume
- 7
- Issue
- 5
- Pages
- e37887
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3364277
- OpenAlex
- W2085568044
- Cited by
- 404
- References
- 33
- Citations by year
- 2026: 16 · 2025: 15 · 2024: 20 · 2023: 14 · 2022: 21 · 2021: 36 · 2020: 22 · 2019: 44 · 2018: 41 · 2017: 37 · 2016: 28 · 2015: 26 · 2014: 32 · 2013: 46 · 2012: 6
- FWCI
- 34.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Jyväskylä University Digital Archive (University of Jyväskylä) (submittedVersion, cc-by)
- Scholar Commons (University of South Carolina) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (NIH T32)
- National Institute on Aging (R01AG017474, R01AG015389, NIH T32 AG00068)
- National Heart, Lung, and Blood Institute (R01HL047327, R01HL047317, R01HL057354, R01HL066262, R01HL047323, R01HL045670, R01HL047321)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32AR048523)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Physical Activity and Health
- Health Sciences › Medicine › Physiology (medical) › Cardiovascular and exercise physiology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- diabetes risk factors, fasting insulin, systolic blood pressure, HDL cholesterol, triglycerides, within-person variability, exercise prescription, racial differences, HERITAGE Family Study
- MeSH terms
- Adult, Aged, Basal Metabolism, Blood Pressure, Cardiovascular Diseases, Diabetes Mellitus, Exercise Therapy, Fasting, Female, Humans, Insulin, Cholesterol, HDL, Male, Metabolism, Middle Aged, Risk Factors, Triglycerides, Exercise, Epidemiologic Studies
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-12, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-12 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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