Genetics, gene polymorphism, and exercise performance 1

2 Design of genetic studies -1

3 Design of genetic studies -2

4 Familial aggregation of VO2max

5 Performance/fitness phenotypes Fast growing after completion of Human Genome Project >170 genes associated with performance or health-related fitness in 2006 Only 29 in 2001 Updated every year in review papers

6 Genes may affect performance, fitness Bray, 2009

Genes may affect performance, fitness 7 Bray, 2009

Genes may affect performance, fitness 8 Bray, 2009

Mitochondrial genes may affect performance, fitness 9 Bray, 2009

Ex Biochem c4- genome Genes Show a Wide Distribution of Sizes Most genes are uninterrupted in yeasts, but are interrupted in higher eukaryotes. Figure 3.10

11 Single nucleotide polymorphism (SNP) 單核甘酸多型性 can affect how humans develop diseases, respond to pathogens, chemicals, drugs, vaccines... Personalized medicine comparing regions of the genome between cohorts

Ex Biochem c4- genome 12

Ex Biochem c4- genome 13

Ex Biochem c4- genome 14

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Ex Biochem c4- genome 16

Ex Biochem c4- genome 17

Ex Biochem c4- genome 18

Ex Biochem c4- genome 19

20 ACE polymorphism in Olympic runners

21 ACE and endurance performance Angiotension-converting enzyme Angiotensinogen  angiotensin II, vacoconstrictor 287 nucleotide insertion/deletion polymorphism Effect of genotypes on VO2max inconsistent Greater muscle efficiency in I/I compated to D/D Efficiency: Work performed per unit energy expenditure No association at baseline: potential gene x environment interaction Trainability D allele: ↑muscle growth?

Ex Biochem c9- genetics 22

Ex Biochem c9- genetics 23

24 ACTN3 and muscle performance Alpha-actinin 3 R577X (arginine  stop codon at codon 577) X-allele frequency 25-50% in different populations In patients with several muscular disorders: X/X genotype complete absence of ACTN3 protein Only by chance, ACTN deficiency not deleterious because its function can be compensated by ACTN2 X/X reduce performance in sprint or power-related sports

Ex Biochem c9- genetics 25

26 Myostatin and muscle mass Disabled myostatin gene increase muscle size Mutation rare in humans _uu8o

27 Myostatin mutations in animals

Ex Biochem c9- genetics 28

Gene polymorphism in power athletes 29 Ruiz et al, 2010

Gene polymorphism in power athletes 30 Ruiz et al, 2010

Gene polymorphism and muscular strength 31 Leuven Genes for Muscular Strength Study, 283 male siblings aged 17–36 yr in 105 families, maximal isometric and concentric knee strength in isokinetic Mars, 2008

Genetics and trainability HERITAGE cohort had reduced its HR response to a 50 watt cycle ergometer work rate by an average of 11 bpm as a result of 20 weeks of endurance training interindividual variation around this average response was substantial bpm this training-induced HR adaptation aggregated in families maximal heritability estimated 34% 32 Perusse, 2013

Gene polymorphism and trainability 33 Perusse et al, 2013

Stepwise regression for standardized residuals of VO2max training response 34 HERITAGE FAMILY STUDY, Hagberg, 2011

Genetics and effect of exercise on diseases gene polymorphisms play a crucial role in determination of the improvement of risk factors for lifestyle-related diseases following exercise training. 35

Exercise and gene interaction on BP 36 Roth, 2012

Change in BMI after 10-month training in obese subjects 37 Mori, 2009

N of BMI-increasing alleles vs BMI in active and non-active 38 Hagberg, 2011

Carotid stiffness in different fitness groups and MTHFR gene polymorphism 39 Hagberg, 2011

Adverse effects of exercise program? Personalized intervention 40 Perusse, 2013 Exercise-induced changes in fasting insulin, HDL-C, TG, SBP

41 Molecular scouting? Exercise is a very complicated physiological function May involve more than 1 gene > 100 genes turn on/off after a single bout of exercise Need to look for combination of genes Current techniques available Gene chips, computer aided

中國游泳選手基因與傳統選才 42

中國游泳選手基因與傳統選才 43

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Nature vs nurture due to inherent human degeneracy, there are many different trajectories to achieving elite athletic performance Degeneracy: non-isomorphic components producing isofunctional outcomes While the greatest training responses may be theoretically associated with the most favorable genotypes being exposed to highly specialized training environments, this is a rare and complex outcome. Both nature and nurture are important 46

47 Gene therapy and gene doping Gene therapy successfully used in several clinical conditions Somatic cell gene therapy Germ cell gene therapy Gene doping: possible and may already being used 2006, a German coach asked for Repoxygen, a virus- based gene therapy product designed to deliver human EPO gene to muscle cells Originally used to treat severe anemia, successful in treating mice Almost impossible to detect Tissue sampling, DNA sequence

Ex Biochem c9- genetics 48

Acute muscle contraction influence gene expression 49 Kostek, 2007

Acute muscle contraction influence gene expression 50 Kostek, 2007

Expression levels in PBMC after 30 min exercise 51 Radom-Aizik, 2008