ACTN3 R577X genotype affects training-induced changes in mitochondrial respiration in humans

X. Yan,^1,2 N. Eynon,^1,2 I.D. Papadimitriou,¹ J. Kuang,¹ O. Tirosh,¹ L. O’Keefe,¹ M. Anderson,¹ K.N. North² and D.J. Bishop,¹ ¹Institute of Sport, Exercise and Active Living (ISEAL), Victoria University, Melbourne, VIC 8001, Australia and ²Murdoch Childrens Research Institute, The Royal Children's Hospital, Melbourne, VIC 3052, Australia.

Individual differences in the response to similar exercise training are a well-known occurrence, and are influenced by both environmental and genetic factors. The common null polymorphism (R577X) in the ACTN3 gene, which results in absence of α-actinin-3 in more than one billion humans worldwide (MacArthur & North, 2007), is a strong candidate to influence muscle performance and mitochondrial adaptations to training. The ACTN3 R577X variant has previously been associated with athletic performance and the response to exercise training in both humans (Eynon et al., 2013) and mice (Seto et al., 2013). It has also been shown that the activity of mitochondrial (citrate synthase, succinate dehydrogenase, cytochrome C oxidase) enzymes are higher in α-actinin-3 deficient mice (ACTN3 577XX genotype) (MacArthur et al., 2007,2008). However, little is known about how the ACTN3 R577X variant influences training-induced changes in mitochondrial function in humans.

Aim. To investigate the influence of ACTN3 genotype on performance outcomes and mitochondrial respiration following 4 weeks of High-Intensity Interval Training (HIIT).

Methods. We have recruited ten moderately-trained Caucasian males (age=32.6±1.2), who were either homozygous for α-actinin-3 deficiency (ACTN3 XX genotype, n=5), or homozygous for the R allele (ACTN3 RR genotype n=5). Participants in each group were matched for physical activity levels and body mass index (BMI). Subsequently, participants underwent 4 weeks of HIIT, 3 times per week. A 20 km time-trial (20km TT), and a graded exercise test (GXT), to assess peak oxygen uptake (VO_2Peak) and the Lactate threshold (LT), were performed pre and post training. Pre and post training, a resting muscle biopsy was taken from the vastus lateralis muscle and analysed for in situ mitochondrial respiration (Bishop et al., 2010).

Results. Following 4 weeks of HIIT, the ACTN3 577XX participants showed a greater increase in maximal mitochondrial respiration (Vmax) (XX = 14.43 pmol s⁻¹ mg⁻¹ ww, RR = 6.11 pmol s⁻¹ mg⁻¹ ww, see Figure). Furthermore, the 577XX participants showed a higher increase (improved) in LT, following HIIT compared with their RR counterparts (LT XX = 18.7 W, LT RR=17.0 W). In contrast, the ACTN3 577RR participants recorded greater increases in 20km TT performance (3 min and 20s) than their ACTN3 577XX counterparts (48 s).

Maximal mitochondrial respiration (Vmax) across ACTN3 genotypes pre and post exercise training.

Conclusion. These preliminary results indicate at ACTN3 577XX individuals had a greater increase in both maximal mitochondrial respiration and the LT than their 577RR counterparts. Due to the small sample size tested to date, none of the differences reached statistical significance. However, our data raise the possibility that the ACTN3 R577X variant influences training-induced improvement in both mitochondrial function and LT. These results also support recent data from our lab suggesting a disassociation between changes in mitochondrial respiration and endurance performance.

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