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[Association of the mitochondrial transcription factor (TFAM) gene polymorphism with physical performance of athletes]

Authors:
  • Institute of Biomedical Problems of the Russian Academy of Sciences
  • Federal Science Center of Physical Culture and Sport (VNIIFK)
  • Institute of Bio-medical Problems, Russian Academy of Sciences, Moscow, Russia

Abstract

The aim of the study was to investigate allelic distribution of the mitochondrial transcription factor gene (TFAM) Ser12Thr polymorphism in athletes (n = 1537) and controls (n = 1113), and to find interrelation between genotypes and aerobic capacity in rowers (n = 90). Genotyping was performed by restriction fragment length polymorphism analysis. Aerobic capacity (maximal oxygen consumption (VO2max) and maximal power production capacity (Wmax)) was determined using an incremental test to exhaustion by rower ergometer. The frequency of TFAM 12Thr allele was significantly higher in endurance-oriented athletes (n = 588) than in controls (14.0% vs. 9.1%; p <0.0001), and increased with the growth of skills. Furthermore, TFAM 12Thr allele was associated with high values of aerobic performance (when Wmax and VO2max were measured). Thus, TFAM gene Ser12Thr polymorphism is associated with physical performance of athletes.
ФИЗИОЛОГИЯ ЧЕЛОВЕКА, 2010, том 36, № 2, с. 121–125
121
Митохондриям принадлежит ведущая роль в
образовании энергии, которая необходима для
выполнения пролонгированных физических
упражнений. Митохондриальный геном человека
кодирует 13 белков – компонентов энзиматиче
ских систем окислительного фосфорилирования,
гены двух рибосомальных и 22 транспортных
РНК [1]. Поддержание оптимального количества
митохондриальной ДНК (мтДНК) и экспрессии
ее генов – необходимое условие для осуществле
ния энергообеспечения мышечной деятельности
аэробным путем.
Ген митохондриального транскрипционного
фактора (
TFAM
; локализация: 10
q
21) кодирует
ключевой белок, ответственный за регуляцию ре
пликации и транскрипции ДНК митохондрий и
защищает клетки от оксидативного стресса (что
может иметь большое значение в развитии нейро
дегенеративных заболеваний) [2, 3]. Аэробные
физические нагрузки приводят к увеличению
экспрессии
TFAM
и количества копий мтДНК [4–
6]. Также установлено, что сверхэкспрессия гена
Tfam
в кардиомиоцитах крысы сопровождается
более чем двукратным увеличением количества
копий мтДНК и повышением продукции АТФ
[7]. В свою очередь, нокаутированные по
Tfam
мыши проявляют мышечную слабость в связи с
нарушением накопления ионов кальция сарко
плазматическим ретикулумом [8]. Кроме того,
экспериментальное снижение количества
Tfam
в
адипоцитах с помощью РНКинтерференции
приводит к нарушению углеводного обмена, сни
жению базального уровня потребления кислоро
да и продукции АТФ [9]. Экспрессия
TFAM
регу
лируется такими транскрипционными фактора
ми как
NRF
1 и
NRF
2
A
.
В 1м экзоне гена
TFAM
обнаружен
rs
1937
G/C
полиморфизм, приводящий к замене серина на
треонин в 12м кодоне митохондриального
транскрипционного фактора (
Ser
12
Thr
). Редкий
TFAM
12
Thr
аллель является протективным в от
ношении развития болезни Альцгеймера [10, 11]
и гипертрофии миокарда левого желудочка у рос
сийских гребцовакадемистов и конькобежцев
[12], а также ассоциируется со способностью к
длительной физической работе дайверов в тесте
на тредмиле [13].
В связи с физиологической ролью митохон
дриального транскрипционного фактора особый
интерес представляет собой выявление взаимо
связи
Ser
12
Thr
полиморфизма гена
TFAM
с физи
ческой работоспособностью спортсменов. Мож
но предположить, что частота
TFAM
12
Thr
аллеля
превалирует у спортсменов, тренирующих каче
АССОЦИАЦИЯ ПОЛИМОРФИЗМА ГЕНА МИТОХОНДРИАЛЬНОГО
ТРАНСКРИПЦИОННОГО ФАКТОРА (
TFAM
) C ФИЗИЧЕСКОЙ
РАБОТОСПОСОБНОСТЬЮ СПОРТСМЕНОВ
© 2010 г. И. И. Ахметов*
,
**, Д. В. Попов*,
С. С. Миссина*, О. Л. Виноградова*, В. А. Рогозкин**
*ГНЦ РФ – Институт медикобиологических проблем РАН, Москва
**СанктПетербургский НИИ физической культуры
Поступила в редакцию 16.06.2009 г.
Цель настоящего исследования заключалась в изучении распределения частоты аллелей по
Ser
12
Thr
полиморфизму гена митохондриального транскрипционного фактора (
TFAM
) у спортсменов (
n
=
= 1537) и в контрольной группе (
n
= 1113), а также в выявлении взаимосвязи генотипов с аэробной
работоспособностью у гребцовакадемистов (
n
= 90). Генотипирование осуществляли с помощью
анализа полиморфизма длин рестрикционных фрагментов. Аэробную работоспособность (макси
мальное потребление кислорода
МПК и максимальную аэробную мощность
W
max
) определяли
в тесте с возрастающей нагрузкой “до отказа” на гребном эргометре. Частота
TFAM
12
Thr
аллеля в
группе спортсменов, преимущественно развивающих качество выносливости (
n
= 588), была значи
мо выше, чем в контрольной выборке (14.0% против 9.1%;
p
< 0.0001), и повышалась по мере роста
спортивной квалификации. Кроме того, выявлена взаимосвязь
TFAM
12
Thr
аллеля с высокой
аэробной работоспособностью спортсменов (по данным
W
max
и МПК). Таким образом,
Ser
12
Thr
полиморфизм гена
TFAM
ассоциируется с физической работоспособностью спортсменов.
Ключевые слова
:
TFAM
, физическая работоспособность, ген, полиморфизм.
УДК 575.1, 576.311.347, 612.744.2, 612.76
122
ФИЗИОЛОГИЯ ЧЕЛОВЕКА том 36 № 2 2010
АХМЕТОВ и др.
ство выносливости, а
TFAM
Ser
/
Thr
и
Thr
/
Thr
ге
нотипы ассоциируются с более высокими значе
ниями аэробной работоспособности. Для провер
ки данной гипотезы нами определена частота
TFAM
12
Thr
аллеля у спортсменов различной спе
циализации и квалификации. В качестве модели
для исследования физической работоспособно
сти выбрана академическая гребля, представляю
щая собой сложную спортивную дисциплину и
требующая от спортсмена в первую очередь про
явления выносливости (прохождение гребцами
академистами дистанции 2000 метров на 70% обес
печивается за счет аэробного метаболизма) [14].
Цель настоящего исследования заключалась в
изучении распределения частоты аллелей гена
TFAM
у спортсменов и в контрольной группе, а
также в выявлении взаимосвязи генотипов по
TFAM
с аэробной работоспособностью у гребцов
академистов.
МЕТОДИКА
В исследовании приняли участие 1537 спортс
менов, занимающихся различными видами спор
та (женщины 20.7
±
0.4 лет,
n
= 452, мужчины
24.2
±
2.3 лет,
n
= 1085).
В соответствии с типом энергообеспечения
тренировочной нагрузки мы разделили цикличе
ские виды спорта на 5 групп, в которых физиоло
гические закономерности используемых в трени
ровочном процессе упражнений одинаковы [15].
Помимо признаков, характеризующих развитие
выносливости, быстроты и силы, принимали во
внимание мощность выполняемой на трениров
ках работы, с разделением на максимальную, суб
максимальную, большую, умеренную и перемен
ную, а также цикличность нагрузки с разделени
ем на циклическую и ациклическую работу
(таблица).
На момент получения биологического матери
ала для генотипирования 60 спортсменов явля
лись заслуженными мастерами спорта (ЗМС),
171 – мастерами спорта международного класса
(МСМК), 304 – мастерами спорта (МС), 459 –
кандидатами в мастера спорта (КМС) и
543 спортсмена имели взрослый разряд.
В рамках физиологического обследования
90 гребцамакадемистам (56 мужчин (27 КМС,
29 МС), 34 женщины (13 КМС, 21 МС)) тестиро
вали показатели аэробной и анаэробной работо
способности. Испытуемые были предупреждены
об условиях эксперимента и дали письменное со
глашение на добровольное участие в нем. Экспе
римент был одобрен Физиологической секцией
Российской Национальной комиссии по биоло
гической этике.
Контрольная группа состояла из 1113 человек,
жителей СанктПетербурга, Москвы и Набереж
ных Челнов (женщины 18
±
0.1 лет,
n
= 587, муж
чины 17.6
±
0.1 лет,
n
= 526). Главным условием
для включения испытуемых в контрольную груп
пу являлось отсутствие стажа регулярных занятий
какимилибо видами спорта (по данным анкети
рования респонденты не указывали на наличие
спортивного разряда).
Для молекулярногенетического анализа ис
пользовали образцы ДНК испытуемых, выделен
ных методом щелочной экстракции [16] или сор
бентным методом, в соответствии с прилагаемой
инструкцией по применению к комплекту “ДНК
сорбА” (Центральный НИИ эпидемиологии МЗ
РФ), в зависимости от способа забора биологиче
ского материала (смыв либо соскоб эпителиаль
ных клеток ротовой полости).
Анализ полиморфизма длин рестрикционных
фрагментов (ПДРФ) проводили следующим обра
зом. Для определения
Ser
12
Thr
полиморфизма гена
TFAM
использовали двухпраймерную систему (пря
мой праймер – 5'
CCAGGAGGCTCTCCGAGATTGG
3';
обратный праймер – 5'
ACCAGGGTGACTCTGAACTC
CTA
3'). Для гидролиза ампликонов длиной
267 пар нуклеотидов (п.н.) применяли фермент
BstDEI (“СибЭнзим”).
Ser
12 аллелю соответству
ют фрагменты длиной 184 и 83 п.н., а 12
Thr
алле
лю – 267 п.н. Анализ длин рестрикционных фраг
ментов продуктов проводили путем электрофоре
тического разделения в 8% полиакриламидном
геле с последующей окраской бромистым этиди
ем и визуализацией в проходящем ультрафиоле
товом свете при помощи трансиллюминатора
“ETS VilberLourmat” (Франция).
Определение аэробных возможностей в тесте с
нарастающей нагрузкой производили на механи
ческом гребном эргометре PM 3 (Concept II,
США). Начальная нагрузка составила 150 Вт для
мужчин и 100 Вт – для женщин, длительность
ступени 3 мин, время отдыха между ступенями
30 с. Работа выполнялась до отказа (снижение
мощности гребка > 30 Вт от заданной мощности,
дыхательный коэффициент >1.1). Поскольку
спортсмены не всегда могли проработать на по
следней ступени 3 мин полностью, за максималь
ную мощность (
W
max
) принималось расчетное
значение:
где
W
n
– средняя мощность последней ступени
(Вт);
W
n –
1
– средняя мощность предпоследней
ступени (Вт);
t
n
– время работы на последней сту
пени (с).
Во время теста постоянно (каждый дыхатель
ный цикл) регистрировали показатели газообме
на и частоту сердечных сокращений (ЧСС,
уд/мин) (газоанализатор MetaMax 3B, Cortex,
Германия и Vmax 229, SensorMedics, США). Мак
Wmax Wn1
WnWn1
()tn
×
180
,+=
ФИЗИОЛОГИЯ ЧЕЛОВЕКА том 36 № 2 2010
АССОЦИАЦИЯ ПОЛИМОРФИЗМА ГЕНА 123
Распределение абсолютных и относительных частот генотипов и аллелей по
TFAM
среди спортсменов различных
групп и в контрольной группе
Гр у пп а В и д с по р та
n
Генотипы 12
Thr
аллель
Ser
/
Ser Ser
/
Thr Thr
/
Thr
%
p
I Биатлон 34 24 9 1 16.2 0.076
Лыжные гонки 15–50 км 78 53 24 1 16.7 0.0029*
Спортивная ходьба 24 16 7 1 18.8 0.042*
Марафон 6 6 0 0 0 0.55
Велошоссе 109 80 28 1 13.8 0.033*
Плавание 5–25 км 21 17 4 0 9.5 0.92
Триатлон 29 20 8 1 17.2 0.059
Все 301 216 80 5 15.0 <0.0001*
II Лыжные гонки 5–10 км 64 52 11 1 10.2 0.79
Академическая гребля 193 138 52 3 15.0 0.0004*
Коньки 5–10 км 4 2 2 0 25.0 0.34
Плавание 800–1500 м 26 24 2 0 3.8 0.29
Все 287 216 67 4 13.1 0.0055*
III Гребля на байдарке 35 31 4 0 5.7 0.45
Бег 800–1500 м 14 9 5 0 17.9 0.2
Шорттрек 880000.41
Коньки 1–3 км 9 7 2 0 11.1 0.76
Плавание 200–400 м 27 19 8 0 14.8 0.23
Все 93 74 19 0 10.2 0.69
IV Коньки многоборье 68 59 8 1 7.4 0.59
Горнолыжный спорт 13 12 1 0 3.8 0.56
Спортивная гимнастика 54 43 11 0 10.2 0.83
Баскетбол 33 23 10 0 15.2 0.14
Бокс 36 31 5 0 6.9 0.68
Дайвинг 9 5 3 1 27.8 0.02*
Хоккей с шайбой 16 12 4 0 12.5 0.72
Маунтинбайк 1082010.00.89
Современное пятиборье 19 16 3 0 7.9 0.8
Стрелковый спорт 44 40 4 0 4.5 0.2
Прыжки с трамплина 14 12 2 0 7.1 0.98
Футбол 42 36 5 1 8.3 0.97
Теннис 29 23 5 1 12.1 0.58
Борьба 97 68 27 2 16.0 0.0027*
Все 484 388 90 6 10.5 0.22
V Бодибилдинг 73 57 16 0 11.0 0.54
Прыжки (легкая атлетика) 12 11 1 0 4.2 0.63
Силовое троеборье 2623217.70.92
Бег 100–400 м 122 94 24 4 13.1 0.054
Коньки 500–1000 м 28 21 7 0 12.5 0.52
Плавание 50–100 м 34 30 4 0 5.9 0.49
Метания, толкание ядра 17 16 1 0 2.9 0.35
Тяжелая атлетика 60 47 13 0 10.8 0.63
Все 372 299 68 5 10.5 0.28
Все спортсмены 1537 1193 324 20 11.8 0.0015*
Контрольная группа 1113 919 186 8 9.1 1.00
*
p
< 0.05, статистически значимые различия между группами спортсменов и контрольной выборкой.
124
ФИЗИОЛОГИЯ ЧЕЛОВЕКА том 36 № 2 2010
АХМЕТОВ и др.
симальное потребление кислорода (МПК, л/мин)
определяли по значениям усредненных за послед
ние 30 с каждой ступени теста показателей газо
обмена.
Статистическая обработка данных была вы
полнена с применением компьютерной програм
мы “GraphPad InStat”. Определяли: средние зна
чения (
M
), стандартную ошибку (
±
SEM
) и сред
нее квадратическое отклонение (
s
). Значимость
различий в частоте аллелей между сравниваемы
ми выборками определяли с использованием
критерия
χ
2
(для больших выборок) или точного
теста Фишера (для малых выборок). Сравнение
групп по количественному признаку (физиологи
ческие показатели) проводили с помощью непар
ного теста. Различия считались статистически
значимыми при
p
< 0.05.
РЕЗУЛЬТАТЫ ИССЛЕДОВАНИЯ
И ИХ ОБСУЖДЕНИЕ
1. Анализ распределения частот генотипов и ал
лелей по гену TFAM у спортсменов и в контрольной
группе.
При анализе распределения частот гено
типов и аллелей по
Ser
12
Thr
полиморфизму гена
TFAM
в контрольной группе и у спортсменов по
лучены следующие результаты. Частота
TFAM
12
Thr
аллеля в контрольной группе составляет
9.1%, и при этом она не отличается у женщин
(9.4%) и мужчин (9.0%). Наблюдаемое в кон
трольной выборке распределение генотипов
Ser
/
Ser
(82.6%),
Ser
/
Thr
(16.7%) и
Thr
/
Thr
(0.7%)
подчиняется равновесию ХардиВайнберга (
χ
2
=
=0.07;
df
= 2,
p
= 0.96) (таблица).
Частота
TFAM
12
Thr
аллеля в общей группе
спортсменов значимо выше, чем в контрольной
выборке (11.8% против 9.1%;
p
= 0.0015). Распре
деление генотипов
Ser
/
Ser
(77.6%),
Ser
/
Thr
(21.1%) и
Thr
/
Thr
(1.3%) в группе спортсменов
также подчиняется равновесию ХардиВайнберга
(
χ
2
= 0.05;
df
= 2,
p
= 0.97). В таблице представле
ны данные о распределении генотипов и аллелей
по гену
TFAM
у спортсменов различных по типу
энергообеспечения специализаций. Как видно,
только в I и II группах, в которые входят виды
спорта, преимущественно развивающие качество
выносливости, частота
TFAM
12
Thr
аллеля значи
мо выше, чем в контрольной группе (суммарная
частота
TFAM
12
Thr
аллеля для двух групп: 14.0%;
p
< 0.0001 по сравнению с контролем). При де
тальном рассмотрении можно отметить, что зна
чимые различия в частоте
TFAM
12
Thr
аллеля кос
нулись таких спортивных дисциплин, как лыж
ные гонки 15–50 км, спортивная ходьба,
велошоссе, академическая гребля, дайвинг и
борьба.
При анализе распределения аллелей гена
TFAM
по половому признаку, как среди всех
спортсменов, так и среди спортсменов I–II групп,
различий обнаружено не было (все спортсмены:
женщины – 11.8%, мужчины – 11.9%; I–II груп
пы: женщины – 14.5%, мужчины – 13.8%).
При оценке распределения частот аллелей в
зависимости от спортивной квалификации обна
ружено, что в группе стайеров (I и II группы
спортсменов) частота
TFAM
12
Thr
аллеля имеет
тенденцию к повышению по мере роста квалифи
кации: разрядники + КМС (13.2%) МС +
+ МСМК (14.6%) ЗМС (25.0%).
Обнаруженная более высокая частота
TFAM
12
Thr
аллеля у стайеров по сравнению с кон
трольной группой и ее повышение с ростом спор
тивной квалификации может свидетельствовать о
том, что носительство
TFAM
12
Thr
аллеля благо
приятствует развитию и проявлению выносливо
сти.
2. Выявление взаимосвязи физиологических по
казателей с генотипами по TFAM у спортсменов.
Обнаружение значительных различий в некото
рых физиологических показателях между гребца
миакадемистами разного пола и квалификации
обусловило проведение раздельного анализа вза
имосвязи фенотипов с генотипическими данны
ми. В связи с этим из 90 спортсменов были сфор
мированы 4 подгруппы (мужчины КМС (
n
= 27),
мужчины МС (
n
= 29), женщины КМС (
n
= 13),
женщины МС (
n
= 21)).
Средние значения
W
max
были значимо выше у
мужчинМС, носителей
TFAM
12
Thr
аллеля по
сравнению с носителями
TFAM
Ser
/
Ser
генотипа
(
Ser
/
Thr
+
Thr
/
Thr
– 421 (48) Вт,
Ser
/
Ser
– 376 (34)
Вт;
p
= 0.01). Кроме того,
TFAM
12
Thr
аллель ассо
циировался с более высокими значениями МПК
у мужчинМС (
Ser
/
Thr
+
Thr
/
Thr
– 5.47
(0.7) л/мин,
Ser
/
Ser
– 4.95 (0.47) л/мин;
p
= 0.057).
Полученные результаты согласуются с ранее
опубликованными нами данными, где была пока
зана ассоциация с
TFAM
12
Thr
аллеля с низким
риском развития гипертрофии миокарда левого
желудочка (фактор, лимитирующий производи
тельность сердечнососудистой системы) у
спортсменов [12] и высокой физической работо
способностью дайверов [13]. Все эти данные поз
воляют отнести
TFAM
12
Thr
аллель к генетиче
ским маркерам, ассоциированным с предраспо
ложенностью к занятиям видами спорта,
направленными на преимущественное развитие
выносливости. Таких генетических маркеров по
состоянию на 2009 год насчитывается не менее
35 [17].
Функциональная значимость
Ser
12
Thr
поли
морфизма гена
TFAM
не изучена, хотя и предпо
лагается, что замена серина на треонин в 12м по
ложении может привести к изменениям физико
химических свойств белкового продукта, и, сле
довательно, повлиять на транскрипцию регули
ФИЗИОЛОГИЯ ЧЕЛОВЕКА том 36 № 2 2010
АССОЦИАЦИЯ ПОЛИМОРФИЗМА ГЕНА 125
руемых
TFAM
генов. Дальнейшие исследования, в
том числе
in vitro
, могут прояснить этот вопрос.
ЗАКЛЮЧЕНИЕ
Таким образом,
Ser
12
Thr
полиморфизм гена
TFAM
ассоциируется с физической работоспособ
ностью спортсменов и играет важную роль в спор
тивном отборе. Результаты проведенного исследо
вания могут иметь прикладное значение в плане
подбора оптимальной спортивной специализации
и профессиональной подготовки спортсменов.
Работа получила финансовую поддержку
Минобрнауки России (ГК от 27 апреля 2007 г.
№ 02.522.11.2004).
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ü
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Alvarez V., Corao A.I., AlonsoMontes C. et al.
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Bolla M.K., Haddad L., Humphries S.E. et al.
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Collins M. (Med. Sport Sci.) Basel, Karger, 2009. V. 54.
P. 43.
Association of the Mitochondrial Transcription Factor (
TFAM
) Gene Polymorphism
with Physical Performance of Athletes
I. I. Ahmetov, D. V. Popov, S. S. Missina, O. L. Vinogradova, and V. A. Rogozkin
The aim of the study was to investigate allelic distribution of the mitochondrial transcription factor gene
(
TFAM
)
Ser
12
Thr
polymorphism in athletes (
n
= 1537) and controls (
n
= 1113), and to find interrelation be
tween genotypes and aerobic capacity in rowers (
n
= 90). Genotyping was performed by restriction fragment
length polymorphism analysis. Aerobic capacity (maximal oxygen consumption (VO
2max
) and maximal pow
er production capacity (
W
max
)) was determined using an incremental test to exhaustion by rower ergometer.
The frequency of
TFAM
12
Thr
allele was significantly higher in enduranceoriented athletes (
n
= 588) than
in controls (14.0% vs. 9.1%;
p
< 0.0001), and increased with the growth of skills. Furthermore,
TFAM
12
Thr
allele was associated with high values of aerobic performance (when
W
max
and VO
2max
were measured). Thus,
TFAM
gene
Ser
12
Thr
polymorphism is associated with physical performance of athletes.
Key words
:
TFAM
, physical performance, gene, polymorphism.
... As a result of training, the number of mitochondria in skeletal muscles increases, which increases their energy potential and reduces fatigability. At the same time, the TFAM transcription factor activity is the most important mechanism of mitochondrial biogenesis regulation in myocytes [51]. The protein is expressed in various organs and tissues, including skeletal muscles and heart muscles ( Figure 7b). ...
... The protein is expressed in various organs and tissues, including skeletal muscles and heart muscles ( Figure 7b). supply of muscle activity [51]. 530 Sports activities (aerobic or anaerobic) cause a change in molecular expression in 531 skeletal muscles, which contributes to the adaptation of muscle tissue to the requirements 532 of physical stress [52]. ...
... The human mitochondrial genome encodes 13 proteins-components of enzymatic systems of oxidative phosphorylation, genes of two ribosomal and 22 transport RNAs. Maintaining the optimal amount of mitochondrial DNA (mtDNA) and the expression of its genes is a prerequisite for the aerobic energy supply of muscle activity [51]. ...
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