Association Between The ACTN3 (R577X) Genotype And Oxidative Capacity Of Fast Muscle Fibers In Humans

Abstract

About 18% of Western European populations have a complete deficiency of the alpha-actinin-3 protein due to homozygosity for a stop codon mutation (577X) in the ACTN3 gene. The alpha-actinin-3 protein has an important function in the Z-line of the sarcomere where it binds the thin actin filaments. The 577XX null genotype seems to be beneficial for sustained muscle contractions, indicated by increased X-allele carriers in elite endurance athletes, while RR genotype carriers outperform XX carriers for high velocity contractions. Recently MacArthur et al. provided a mechanistic explanation for these findings with detailed studies of an Actn3-/- mouse model. Mice lacking alpha-actinin-3 showed reduced fast fiber diameter, increased activity of multiple enzymes in the aerobic metabolic pathway, altered contractile properties, and enhanced recovery from fatigue. PURPOSE: To replicate findings in Actn3-/- mice fast muscle -showing a shift towards those characteristic of slow fibers- in human muscle. The purpose of this study was to compare the fiber-specific oxidative capacity of fast and slow muscle fibers in humans with a different ACTN3 R577X genotype. METHODS: 90 healthy young men (18-29 yr) were genotyped for ACTN3 R577X. Twenty-two XX and twenty-two RR subjects underwent a muscle biopsy of the right vastus lateralis muscle at rest. The oxidative capacity marker succinate dehydrogenase (SDH) was measured in a fiber type specific assay using immunohistochemistry. RESULTS: We found no significant differences in SDH staining in fast fibers comparing XX and RR carriers: XX carriers show only 0.5% increased staining for IIa fibers and 6% for IIx fibers (P > 0.37). Furthermore, non-significant group differences (P = 0.27) were found for SDH staining in the slow type I fibers. A significantly higher SDH activity was found in slow fibers compared to fast muscle fibers (P < 0.01), with equal differences for both genotype groups (type I fibers 44% higher than type II fibers in XX vs. 43% higher in RR carriers). CONCLUSIONS: At present, we are unable to confirm a shift in oxidative capacity of fast muscle fibers as reported in an Actn3-/- knockout mouse in our human samples. The presence of different physiological mechanisms and morphological characteristics of muscle fibers in rodents compared to humans might explain these findings.