Selectively breeding for high voluntary physical activity in female mice does not bestow inherent characteristics that resemble eccentric remodeling of the heart, but the mini-muscle phenotype does

Eric C. Leszczynski, Nicole E. Schwartz, Ashley C. McPeek, Katharine D. Currie, David P. Ferguson, Theodore Garland Jr.

Sports Medicine and Health Science ›› 2023, Vol. 5 ›› Issue (3) : 205-212. DOI: 10.1016/j.smhs.2023.07.003
Original article

Selectively breeding for high voluntary physical activity in female mice does not bestow inherent characteristics that resemble eccentric remodeling of the heart, but the mini-muscle phenotype does

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Abstract

Physical activity engagement results in a variety of positive health outcomes, including a reduction in cardiovascular disease risk partially due to eccentric remodeling of the heart. The purpose of this investigation was to determine if four replicate lines of High Runner mice that have been selectively bred for voluntary exercise on wheels have a cardiac phenotype that resembles the outcome of eccentric remodeling. Adult females (average age 55 days) from the 4 High Runner and 4 non-selected control lines were anaesthetized via vaporized isoflurane, then echocardiographic images were collected and analyzed for structural and functional differences. High Runner mice in general had lower ejection fractions compared to control mice lines (2-tailed p ​= ​0.023 6) and tended to have thicker walls of the anterior portion of the left ventricle (p ​= ​0.065). However, a subset of the High Runner individuals, termed mini-muscle mice, had greater ejection fraction (p ​= ​0.000 6), fractional shortening percentage (p ​< ​0.000 1), and ventricular mass at dissection (p ​< ​0.002 7 with body mass as a covariate) compared to non-mini muscle mice. Mice from replicate lines bred for high voluntary exercise did not all have inherent positive cardiac functional or structural characteristics, although a genetically unique subset of mini-muscle individuals did have greater functional cardiac characteristics, which in conjunction with their previously described peripheral aerobic enhancements (e.g., increased capillarity) would partially account for their increased V˙ O2max.

Keywords

Echocardiography / Heart / Voluntary physical activity / Cardiovascular disease / Wheel running

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Eric C. Leszczynski, Nicole E. Schwartz, Ashley C. McPeek, Katharine D. Currie, David P. Ferguson, Theodore Garland Jr.. Selectively breeding for high voluntary physical activity in female mice does not bestow inherent characteristics that resemble eccentric remodeling of the heart, but the mini-muscle phenotype does. Sports Medicine and Health Science, 2023, 5(3): 205‒212 https://doi.org/10.1016/j.smhs.2023.07.003

References

[[1]]
WE Kraus, KE Powell, WL Haskell, et al.. Physical activity, all-cause and cardiovascular mortality, and cardiovascular disease. Med Sci Sports Exerc, 51 (6) ( 2019), pp. 1270-1281, DOI: 10.1249/MSS.0000000000001939
[[2]]
M Zhao, SP Veeranki, S Li, LM Steffen, B. Xi. Beneficial associations of low and large doses of leisure time physical activity with all-cause, cardiovascular disease and cancer mortality: a national cohort study of 88,140 US adults. Br J Sports Med, 53 (22) ( 2019), pp. 1405-1411, DOI: 10.1136/bjsports-2018-099254
[[3]]
PT Williams. Dose-response relationship of physical activity to premature and total all-cause and cardiovascular disease mortality in walkers. PLoS One, 8 (11) ( 2013), Article e78777, DOI: 10.1371/journal.pone.0078777
[[4]]
JT Lightfoot, EJC De Geus, FW Booth, et al.. Biological/genetic regulation of physical activity level: consensus from GenBioPAC. Med Sci Sports Exerc, 50 (4) ( 2018), p. 863, DOI: 10.1249/mss.0000000000001499
[[5]]
N Humpel, N Owen, E. Leslie. Environmental factors associated with adults’ participation in physical activity: a review. Am J Prev Med, 22 (3) ( 2002), pp. 188-199, DOI: 10.1016/s0749-3797(01)00426-3
[[6]]
T. Rowland. Biologic Regulation of Physical Activity, Human Kinetics ( 2016)
[[7]]
T Garland Jr., H Schutz, MA Chappell, et al.. The biological control of voluntary exercise, spontaneous physical activity and daily energy expenditure in relation to obesity: human and rodent perspectives. J Exp Biol, 214 (Pt 2) ( 2011), pp. 206-229, DOI: 10.1242/jeb.048397
[[8]]
JG Swallow, PA Carter, T Garland Jr.. Artificial selection for increased wheel-running behavior in house mice. Behav Genet, 28 (3) ( 1998), pp. 227-237, DOI: 10.1023/a:1021479331779
[[9]]
V Careau, ME Wolak, PA Carter, T Garland Jr.. Limits to behavioral evolution: the quantitative genetics of a complex trait under directional selection. Evolution, 67 (11) ( 2013), pp. 3102-3119, DOI: 10.1111/evo.12200
[[10]]
LE Copes, H Schutz, EM Dlugosz, W Acosta, MA Chappell, T Garland Jr.. Effects of voluntary exercise on spontaneous physical activity and food consumption in mice: results from an artificial selection experiment. Physiol Behav, 149 ( 2015), pp. 86-94, DOI: 10.1016/j.physbeh.2015.05.025
[[11]]
JG Swallow, P Koteja, PA Carter, T Garland Jr.. Food consumption and body composition in mice selected for high wheel-running activity. J Comp Physiol B, 171 (8) ( 2001), pp. 651-659, DOI: 10.1007/s003600100216
[[12]]
L Hiramatsu, T Garland Jr.. Mice selectively bred for high voluntary wheel-running behavior conserve more fat despite increased exercise. Physiol Behav, 194 ( 2018), pp. 1-8, DOI: 10.1016/j.physbeh.2018.04.010
[[13]]
TH Meek, BP Lonquich, RM Hannon, T Garland Jr.. Endurance capacity of mice selectively bred for high voluntary wheel running. J Exp Biol, 212 (18) ( 2009), pp. 2908-2917, DOI: 10.1242/jeb.028886
[[14]]
JG Swallow, T Garland Jr., PA Carter, WZ Zhan, GC. Sieck. Effects of voluntary activity and genetic selection on aerobic capacity in house mice (Mus domesticus). J Appl Physiol ( 1985), 84 (1) ( 1998), pp. 69-76, DOI: 10.1152/jappl.1998.84.1.69
[[15]]
MD Cadney, L Hiramatsu, Z Thompson, et al.. Effects of early-life exposure to Western diet and voluntary exercise on adult activity levels, exercise physiology, and associated traits in selectively bred High Runner mice. Physiol Behav, 234 ( 2021), Article 113389, DOI: 10.1016/j.physbeh.2021.113389
[[16]]
L Hiramatsu, JC Kay, Z Thompson, et al.. Maternal exposure to Western diet affects adult body composition and voluntary wheel running in a genotype-specific manner in mice. Physiol Behav, 179 ( 2017), pp. 235-245, DOI: 10.1016/j.physbeh.2017.06.008
[[17]]
EM Kolb, SA Kelly, KM Middleton, LS Sermsakdi, MA Chappell, T Garland Jr.. Erythropoietin elevates but not voluntary wheel running in mice. J Exp Biol, 213 (3) ( 2010), pp. 510-519, DOI: 10.1242/jeb.029074
[[18]]
T Garland Jr., MT Morgan, JG Swallow, et al.. Evolution of a small-muscle polymorphism in lines of house mice selected for high activity levels. Evolution, 56 (6) ( 2002), pp. 1267-1275, DOI: 10.1111/j.0014-3820.2002.tb01437.x
[[19]]
SA Kelly, TA Bell, SR Selitsky, et al.. A novel intronic single nucleotide polymorphism in the myosin heavy polypeptide 4 gene is responsible for the mini-muscle phenotype characterized by major reduction in hind-limb muscle mass in mice. Genetics, 195 (4) ( 2013), pp. 1385-1395, DOI: 10.1534/genetics.113.154476
[[20]]
GM Bilodeau, H Guderley, DR Joanisse, T Garland Jr.. Reduction of type IIb myosin and IIB fibers in tibialis anterior muscle of mini-muscle mice from high-activity lines. J Exp Zoo A Ecol Genet Physiol., 311 (3) ( 2009), pp. 189-198, DOI: 10.1002/jez.518
[[21]]
DG McGillivray, T Garland Jr., EM Dlugosz, MA Chappell, DA Syme. Changes in efficiency and myosin expression in the small-muscle phenotype of mice selectively bred for high voluntary running activity. J Exp Biol, 212 (7) ( 2009), pp. 977-985, DOI: 10.1242/jeb.026625
[[22]]
H Guderley, P Houle-Leroy, GM Diffee, DM Camp, T Garland Jr.. Morphometry, ultrastructure, myosin isoforms, and metabolic capacities of the “mini muscles” favoured by selection for high activity in house mice. Comp Biochem Physiol B Biochem Mol Biol, 144 (3) ( 2006), pp. 271-282, DOI: 10.1016/j.cbpb.2006.02.009
[[23]]
JC Kay,GC Claghorn, Z Thompson, TG Hampton, T Garland Jr.. Electrocardiograms of mice selectively bred for high levels of voluntary exercise: effects of short-term exercise training and the mini-muscle phenotype. Physiol Behav, 199 ( 2019), pp. 322-332, DOI: 10.1016/j.physbeh.2018.11.041
[[24]]
P Houle-Leroy, H Guderley, JG Swallow, T Garland Jr.. Artificial selection for high activity favors mighty mini-muscles in house mice. Am J Physiol Regul Integr Comp Physiol, 284 (2) ( 2003), pp. R433-R443, DOI: 10.1152/ajpregu.00179.2002
[[25]]
SA Kelly, FR Gomes, EM Kolb, JL Malisch, T Garland Jr.. Effects of activity, genetic selection and their interaction on muscle metabolic capacities and organ masses in mice. J Exp Biol, 220 (6) ( 2017), pp. 1038-1047, DOI: 10.1242/jeb.148759
[[26]]
EL Rezende, T Garland Jr., MA Chappell, JL Malisch, FR Gomes. Maximum aerobic performance in lines of Mus selected for high wheel-running activity: effects of selection, oxygen availability and the mini-muscle phenotype. J Exp Biol, 209 (1) ( 2006), pp. 115-127, DOI: 10.1242/jeb.01883
[[27]]
LE Wong, T Garland Jr., SL Rowan, RT Hepple. Anatomic capillarization is elevated in the medial gastrocnemius muscle of mighty mini mice. J Appl Physiol, 106 (5) ( 2009), pp. 1660-1667, DOI: 10.1152/japplphysiol.91233.2008
[[28]]
R Shave, G Howatson, D Dickson, L. Young.Exercise-induced cardiac remodeling: lessons from humans, horses, and dogs. Vet Sci, 4 (1) ( 2017), p. 9, DOI: 10.3390/vetsci4010009
[[29]]
JC Kay,J Ramirez, E Contreras, T Garland Jr.. Reduced non-bicarbonate skeletal muscle buffering capacity in mice with the mini-muscle phenotype. J Exp Biol, 221 (10) ( 2018), p. jeb172478, DOI: 10.1242/jeb.172478
[[30]]
AA Castro,T Garland, S Ahmed, NC Holt. Trade-offs in muscle physiology in selectively bred high runner mice. J Exp Biol, 225 (23) ( 2022), p. jeb244083, DOI: 10.1242/jeb.244083
[[31]]
DP Ferguson, TO Monroe, CP Heredia, et al.. Postnatal undernutrition alters adult female mouse cardiac structure and function leading to limited exercise capacity. J Physiol, 597 (7) ( 2019), pp. 1855-1872, DOI: 10.1113/JP277637
[[32]]
CR West, MA Crawford, MS Poormasjedi-Meibod, et al.. Passive hind-limb cycling improves cardiac function and reduces cardiovascular disease risk in experimental spinal cord injury. J Physiol, 592 (8) ( 2014), pp. 1771-1783, DOI: 10.1113/jphysiol.2013.268367
[[33]]
EE Schmitt, HL Vellers, WW Porter, JT Lightfoot. Environmental endocrine disruptor affects voluntary physical activity in mice. Med Sci Sports Exerc, 48 (7) ( 2016), pp. 1251-1258, DOI: 10.1249/MSS.0000000000000908
[[34]]
JD Eclarinal, S Zhu, MS Baker, et al.. Maternal exercise during pregnancy promotes physical activity in adult offspring. Faseb J, 30 (7) ( 2016), pp. 2541-2548, DOI: 10.1096/fj.201500018r
[[35]]
EC Leszczynski, JR Visker, DP Ferguson. The effect of growth restriction on voluntary physical activity engagement in mice. Med Sci Sports Exerc, 51 (11) ( 2019), pp. 2201-2209, DOI: 10.1249/mss.0000000000002040
[[36]]
W Acosta, TH Meek, H Schutz, EM Dlugosz, KT Vu, T Garland Jr.. Effects of early-onset voluntary exercise on adult physical activity and associated phenotypes in mice. Physiol Behav, 149 ( 2015), pp. 279-286, DOI: 10.1016/j.physbeh.2015.06.020
[[37]]
DP Ferguson, LJ Dangott, HL Vellers, EE Schmitt, JT Lightfoot. Differential protein expression in the nucleus accumbens of high and low active mice. Behav Brain Res, 291 ( 2015), pp. 283-288, DOI: 10.1016/j.bbr.2015.05.035
[[38]]
DP Ferguson, LJ Dangott, EE Schmitt, HL Vellers, JT Lightfoot. Differential skeletal muscle proteome of high- and low-active mice. J Appl Physiol ( 1985), 116 (8) ( 2014), pp. 1057-1067, DOI: 10.1152/japplphysiol.00911.2013
[[39]]
AM Knab, RS Bowen, AT Hamilton, JT Lightfoot. Pharmacological manipulation of the dopaminergic system affects wheel-running activity in differentially active mice. J Biol Regul Homeost Agents, 26 (1) ( 2012), pp. 119-129
[[40]]
RS Bowen, AM Knab, AT Hamilton, JR McCall, TL Moore-Harrison, JT Lightfoot.Effects of supraphysiological doses of sex steroids on wheel running activity in mice. J Steroids Horm Sci, 3 (2) ( 2012), p. 110, DOI: 10.4172/2157-7536.1000110
[[41]]
JT Lightfoot, L Leamy, D Pomp, et al.. Strain screen and haplotype association mapping of wheel running in inbred mouse strains. J Appl Physiol ( 1985), 109 (3) ( 2010), pp. 623-634, DOI: 10.1152/japplphysiol.00525.2010
[[42]]
AM Knab, JT Lightfoot. Does the difference between physically active and couch potato lie in the dopamine system?. Int J Biol Sci, 6 (2) ( 2010), pp. 133-150, DOI: 10.7150/ijbs.6.133
[[43]]
AM Knab, RS Bowen, AT Hamilton, AA Gulledge, JT Lightfoot. Altered dopaminergic profiles: implications for the regulation of voluntary physical activity. Behav Brain Res, 204 (1) ( 2009), pp. 147-152, DOI: 10.1016/j.bbr.2009.05.034
[[44]]
SA Kelly, DL Nehrenberg, K Hua, T Garland Jr., D. Pomp. Functional genomic architecture of predisposition to voluntary exercise in mice: expression QTL in the brain. Research Support, N.I.H. Extramural Genetics, 191 (2) ( 2012), pp. 643-654, DOI: 10.1534/genetics.112.140509
[[45]]
H MacKay, CA Scott, JD Duryea, et al.. DNA methylation in AgRP neurons regulates voluntary exercise behavior in mice. Nat Commun, 10 (1) ( 2019), pp. 1-11, DOI: 10.1038/s41467-019-13339-3
[[46]]
SE Latchney, MD Cadney, A Hopkins, T. Garland. DNA methylation analysis of imprinted genes in the cortex and hippocampus of cross-fostered mice selectively bred for increased voluntary wheel-running. Behav Genet ( 2022), pp. 1-17, DOI: 10.1007/s10519-022-10112-z
[[47]]
IJ Wallace, T Garland Jr.. Mobility as an emergent property of biological organization: insights from experimental evolution. Evol Anthropol, 25 (3) ( 2016), pp. 98-104, DOI: 10.1002/evan.21481
[[48]]
JG Swallow, JP Hayes, P Koteja, T Garland Jr.. Selection experiments and experimental evolution of performance and physiology. Experiment Evolut: Concepts, Methods Appl Select Experiments ( 2009), pp. 301-351, DOI: 10.1525/california/9780520247666.003.0012
[[49]]
MC Saul, P Majdak, S Perez, M Reilly, T Garland Jr., JS Rhodes. High motivation for exercise is associated with altered chromatin regulators of monoamine receptor gene expression in the striatum of selectively bred mice. Gene Brain Behav, 16 (3) ( 2017), pp. 328-341, DOI: 10.1111/gbb.12347
[[50]]
DA Hillis, L Yadgary, GM Weinstock, et al.. Genetic basis of aerobically supported voluntary exercise: results from a selection experiment with house mice. Genetics, 216 (3) ( 2020), pp. 781-804, DOI: 10.1534/genetics.120.303668
[[51]]
QAT Nguyen, D Hillis, S Katada, et al.. Coadaptation of the chemosensory system with voluntary exercise behavior in mice. PLoS One, 15 (11) ( 2020), Article e0241758, DOI: 10.1371/journal.pone.0241758
[[52]]
AM Bronikowski, PA Carter, TJ Morgan, et al.. Lifelong voluntary exercise in the mouse prevents age-related alterations in gene expression in the heart. Physiol Genom, 12 (2) ( 2003), pp. 129-138, DOI: 10.1152/physiolgenomics.00082.2002
[[53]]
SS Hillman, MS Hedrick. A meta-analysis of in vivo vertebrate cardiac performance: implications for cardiovascular support in the evolution of endothermy. J Exp Biol, 218 (8) ( 2015), pp. 1143-1150, DOI: 10.1242/jeb.118372
[[54]]
GR Scott, AC Dalziel.Physiological insight into the evolution of complex phenotypes: aerobic performance and the O 2 transport pathway of vertebrates. J Exp Biol, 224 (16) ( 2021), p. jeb210849, DOI: 10.1242/jeb.210849
[[55]]
S van der Zwaard, CJ de Ruiter, DA Noordhof, et al.. Maximal oxygen uptake is proportional to muscle fiber oxidative capacity, from chronic heart failure patients to professional cyclists. J Appl Physiol, 121 (3) ( 2016), pp. 636-645, DOI: 10.1152/japplphysiol.00355.2016
[[56]]
JR Gifford, RS Garten, AD Nelson, et al.. Symmorphosis and skeletal muscle: in vivo and in vitro measures reveal differing constraints in the exercise-trained and untrained human. J Physiol, 594 (6) ( 2016), pp. 1741-1751, DOI: 10.1113/jp271229
[[57]]
T Garland Jr., SA Kelly, JL Malisch, et al.. How to run far: multiple solutions and sex-specific responses to selective breeding for high voluntary activity levels. Proc Biol Sci, 278 (1705) ( 2011), pp. 574-581, DOI: 10.1098/rspb.2010.1584
[[58]]
NM Templeman, H Schutz, T Garland Jr., GB McClelland. Do mice bred selectively for high locomotor activity have a greater reliance on lipids to power submaximal aerobic exercise?. Am J Physiol Regul Integr Comp Physiol, 303 (1) ( 2012), pp. R101-R111, DOI: 10.1152/ajpregu.00511.2011
[[59]]
E Abergel, G Chatellier, AA Hagege, et al.. Serial left ventricular adaptations in world-class professional cyclists: implications for disease screening and follow-up. J Am Coll Cardiol, 44 (1) ( 2004), pp. 144-149, DOI: 10.1016/j.jacc.2004.02.057
[[60]]
TE Paterick, T Gordon, D. Spiegel. Echocardiography: profiling of the athlete’s heart. J Am Soc Echocardiogr, 27 (9) ( 2014), pp. 940-948, DOI: 10.1016/j.echo.2014.06.008
[[61]]
C De Innocentiis, F Ricci, MY Khanji, et al.. Athlete’s heart: diagnostic challenges and future perspectives. Sports Med, 48 (11) ( 2018), pp. 2463-2477, DOI: 10.1007/s40279-018-0985-2
[[62]]
KL Weeks, JR McMullen. The athlete’s heart vs. the failing heart: can signaling explain the two distinct outcomes?. Physiology, 26 (2) ( 2011), pp. 97-105, DOI: 10.1152/physiol.00043.2010
[[63]]
DL Prior A. La Gerche. The athlete’s heart. Heart, 98 (12) ( 2012), pp. 947-955, DOI: 10.1136/heartjnl-2011-301329
[[64]]
BJ Maron. Distinguishing hypertrophic cardiomyopathy from athlete’s heart: a clinical problem of increasing magnitude and significance. Heart, 91 (11) ( 2005), p. 1380, DOI: 10.1136/heartjnl-2011-301329
[[65]]
JG Swallow, JS Rhodes, T Garland Jr.. Phenotypic and evolutionary plasticity of organ masses in response to voluntary exercise in house mice. Integr Comp Biol, 45 (3) ( 2005), pp. 426-437, DOI: 10.1093/icb/45.3.426
[[66]]
MB Carlsson, E Trägårdh, H Engblom, et al.. Left ventricular mass by 12-lead electrocardiogram in healthy subjects: comparison to cardiac magnetic resonance imaging. J Electrocardiol, 39 (1) ( 2006), pp. 67-72, DOI: 10.1016/j.jelectrocard.2005.07.005
[[67]]
PW Physick-Sheard, CM Hendren. Heart score: physiological basis and confounding variables. Equine Exerc Physiol, 1 ( 1983), pp. 121-134
[[68]]
CM Hanson, KH Kline, JH Foreman. Measurements of heart scores and heart weights in horses of two different morphic body types. Comp Biochem Physiol A Comp Physiol, 108 (2-3) ( 1994), pp. 175-178, DOI: 10.1016/0300-9629(94)90083-3
[[69]]
EM Kolb, SA Kelly, T Garland Jr.. Mice from lines selectively bred for high voluntary wheel running exhibit lower blood pressure during withdrawal from wheel access. Physiol Behav, 112 ( 2013), pp. 49-55, DOI: 10.1016/j.physbeh.2013.02.010
[[70]]
NJ Palpant, ML Szatkowski, W Wang, et al.. Artificial selection for whole animal low intrinsic aerobic capacity co-segregates with hypoxia-induced cardiac pump failure. PLoS One, 4 (7) ( 2009), Article e6117, DOI: 10.1371/journal.pone.0006117
[[71]]
JG Swallow, AK Wroblewska, RP Waters, KJ Renner, SL Britton, LG Koch. Phenotypic and evolutionary plasticity of body composition in rats selectively bred for high endurance capacity. J Appl Physiol, 109 (3) ( 2010), pp. 778-785, DOI: 10.1152/japplphysiol.01026.2009

The authors wish to thank all members of the Neonatal Nutrition and Exercise Research Lab and ECHO Lab at Michigan State University and the Garland Laboratory at the University of California, Riverside.

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