ACTN3 R577X variant influences mitochondrial-related gene expression following a bout of exercise

I.D. Ppadimitriou,¹ X. Yan,¹ J. Kuang,¹ A. Garnham,¹ K.N. North,² D.J. Bishop¹ and N. Eynon,¹ ¹Institute of Sport, Exercise & Active Living, Victoria University, Melbourne, VIC 8001, Australia and ²Murdoch Childrens Research Institute, 50 Flemington Road, Parkville VIC 3052, Australia.

Background: Mice with α-actinin-3–deficient muscle fibres respond more effectively to endurance exercise training (Seto et al., 2013). This may be related to higher calcineurin activity, which has been reported to induce skeletal muscle mitochondrial biogenesis (Jiang et al., 2010). To date, however, no study has investigated how α-actinin-3 deficiency in humans (ACTN3 XX genotype) regulates mitochondrial-related gene expression in response to a bout of exercise. Potential pathways could involve the downstream targets of calcineurin, such as PGC-1α (Little et al., 2011).

Aim: The purpose of this study was to determine whether the ACTN3 R577X variant influences exercise-induced changes in gene expression.

Methods: Fifteen Caucasian males between 18 and 40 years old, with moderate physical activity levels and a Body Mass Index between 20 and 30, were recruited. Genomic DNA was then extracted from leucocytes, and ACTN3 genotype screening was conducted. Participants were either XX (α-actinin-3 deficient, n=9) or RR (n=6) and, following baseline testing to determine their lactate threshold, performed high-intensity interval exercise bout consisting of 8 × 2-min intervals at 120% of their lactate threshold (interspersed with 1-min rest periods). Muscle samples were collected at rest, immediately after, and 3 h post-exercise for the analysis of mRNA content.

Results: There was an increase in PGC-1α (5.2±2.1 fold for RR and 7.8±3.12 fold for XX), PDK4 (6.6±0.4 fold for RR and 13.0±3.7 fold for XX), and VEGF (1.7±0.37 fold for RR and 2.2±0.6 fold for XX) mRNA content 3 h post exercise. This, however was not statistically significant (P>0.05). There was neither a main effect nor an interaction effect for the mRNA content of COX-1, cytochrome-c or TFAM.

Discussion: There was an increase in PGC-1α, PDK4 and VEGF mRNA content in XX vs RR participants 3 h post exercise. Although not significant, possibly due to the small sample size, this increase was at least 3-fold greater in XX vs RR participants. We are currently recruiting more participants, but these data suggest ACTN3 variant may influence exercise-induced changes in gene expression associated with endurance training.

Seto JT, Quinlan KG, Lek M, Zheng XF, Garton F, MacArthur DG, Hogarth MW, Houweling PJ, Gregorevic P, Turner N, Cooney GJ, Yang N, North KN. (2013). ACTN3 genotype influences muscle performance through the regulation of calcineurin signaling. J Clin Invest 123, 4255-63.

Jiang LQ, Garcia-Roves PM, de Castro Barbosa T, Zierath JR. (2010). Constitutively active calcineurin in skeletal muscle increases endurance performance & mitochondrial respiratory capacity. Am J Physiol Endocrinol Metab 298, E8-E16.

Little JP, Safdar A, Bishop D, Tarnopolsky MA, Gibala MJ. (2011). An acute bout of high-intensity interval training increases the nuclear abundance of PGC-1α and activates mitochondrial biogenesis in human skeletal muscle. Am J Physiol Regul Integr Comp Physiol 300, R1303-10.