Protective role of alpha-actinin-3 in the response to an acute eccentric exercise bout

Vincent B, Windelinckx A, Nielens H, Ramaekers M, Van Leemputte M, Hespel P, Thomis MA. Protective role of alpha-actinin-3 in the response to an acute eccentric exercise bout. J Appl Physiol 109: 564-573, 2010. First published May 27, 2010; doi: 10.1152/japplphysiol.01007.2009.-The ACTN3 gene encodes for the alpha-actinin-3 protein, which has an important structural function in the Z line of the sarcomere in fast muscle fibers. A premature stop codon (R577X) polymorphism in the ACTN3 gene causes a complete loss of the protein in XX homozygotes. This study investigates a possible role for the alpha-actinin-3 protein in protecting the fast fiber from eccentric damage and studies repair mechanisms after a single eccentric exercise bout. Nineteen healthy young men (10 XX, 9 RR) performed 4 series of 20 maximal eccentric knee extensions with both legs. Blood (creatine kinase; CK) and muscle biopsy samples were taken to study differential expression of several anabolic (MyoD1, myogenin, MRF4, Myf5, IGF-1), catabolic (myostatin, MAFbx, and MURF-1), and contraction-induced muscle damage marker genes [cysteine-and glycine-rich protein 3 (CSRP3), CARP, HSP70, and IL-6] as well as a calcineurin signaling pathway marker (RCAN1). Baseline mRNA content of CSRP3 and MyoD1 was 49 +/- 12 and 67 +/- 25% higher in the XX compared with the RR group (P = 0.01-0.045). However, satellite cell number was not different between XX and RR individuals. After eccentric exercise, XX individuals tended to have higher serum CK activity (P = 0.10) and had higher pain scores than RR individuals. However, CSRP3 (P = 0.058) and MyoD1 (P = 0.08) mRNA expression tended to be higher after training in RR individuals compared with XX alpha-actinin-3-deficient subjects. This study suggests a protective role of alpha-actinin-3 protein in muscle damage after eccentric training and an improved stress-sensor signaling, although effects are small

Genome-wide linkage scan for contraction velocity characteristics of knee musculature in the Leuven Genes for Muscular Strength Study

The torque-velocity relationship is known to be affected by ageing, decreasing its protective role in the prevention of falls. Interindividual variability in this torque-velocity relationship is partly determined by genetic factors (h2: 44–67%). As a first attempt, this genome-wide linkage study aimed to identify chromosomal regions linked to the torque-velocity relationship of the knee flexors and extensors. A selection of 283 informative male siblings (17–36 yr), belonging to 105 families, was used to conduct a genome-wide SNP-based (Illumina Linkage IVb panel) multipoint linkage analysis for the torque-velocity relationship of the knee flexors and extensors. The strongest evidence for linkage was found at 15q23 for the torque-velocity slope of the knee extensors (TVSE). Other interesting linkage regions with LOD scores >2 were found at 7p12.3 [logarithm of the odds ratio (LOD) = 2.03, P = 0.0011] for the torque-velocity ratio of the knee flexors (TVRF), at 2q14.3 (LOD = 2.25, P = 0.0006) for TVSE, and at 4p14 and 18q23 for the torque-velocity ratio of the knee extensors TVRE (LOD = 2.23 and 2.08; P = 0.0007 and 0.001, respectively). We conclude that many small contributing genes are involved in causing variation in the torque-velocity relationship of the knee flexor and extensor muscles. Several earlier reported candidate genes for muscle strength and muscle mass and new candidates are harbored within or in close vicinity of the linkage regions reported in the present study

Comprehensive fine mapping of chr12q12-14 and follow-up replication identify activin receptor 1B (ACVR1B) as a muscle strength gene

Muscle strength is important in functional activities of daily living and the prevention of common pathologies. We describe the two-staged fine mapping of a previously identified linkage peak for knee strength on chr12q12-14. First, 209 tagSNPs in/around 74 prioritized genes were genotyped in 500 Caucasian brothers from the Leuven Genes for Muscular Strength study (LGfMS). Combined linkage and family-based association analyses identified activin receptor 1B (ACVR1B) and inhibin β C (INHBC), part of the transforming growth factor β pathway regulating myostatin – a negative regulator of muscle mass – signaling, for follow-up. Second, 33 SNPs, selected in these genes based on their likelihood to functionally affect gene expression/function, were genotyped in an extended sample of 536 LGfMS siblings. Strong associations between ACVR1B genotypes and knee muscle strength (P-values up to 0.00002) were present. Of particular interest was the association with rs2854464, located in a putative miR-24-binding site, as miR-24 was implicated in the inhibition of skeletal muscle differentiation. Rs2854464 AA individuals were ∼2% stronger than G-allele carriers. The strength increasing effect of the A-allele was also observed in an independent replication sample (n=266) selected from the Baltimore Longitudinal Study of Aging and a Flemish Policy Research Centre Sport, Physical Activity and Health study. However, no genotype-related difference in ACVR1B mRNA expression in quadriceps muscle was observed. In conclusion, we applied a two-stage fine mapping approach, and are the first to identify and partially replicate genetic variants in the ACVR1B gene that account for genetic variation in human muscle strength

BsmI polymorphism in the vitamin D receptor gene is associated with leg extensor muscle strength in elderly men

Background and aims: Sarcopenia is defined as a reduction in skeletal muscle mass, strength, and endurance observed with advancing age. Although Vitamin D receptor (VDR) polymorphism is reported to be associated with muscle mass and strength, evidence for this is limited and conflicting. In this study, we examined the association between the polymorphisms of VDR gene BsmI, TaqI and FokI and muscular mass and strength in elderly men. Methods: This is a cross-sectional study conducted in a university hospital. One hundred and twenty men over 65 years of age participated, all participants were active men living independently in Istanbul, who were followed as outpatients in geriatric polyclinics. Most common diagnoses were hypertension, hyperlipidemia, and mild to moderate osteoarthritis. Morbid obese patients were not included in the study. Genomic DNA was extracted from peripheral blood, and VDR genotypes were determined by the polymerase chain reaction. The peak torque of the knee flexors and extensors was measured on a Cybex 350 dynamometer. Body muscle mass was calculated by using bioelectric impedance analysis. Results: The extensor strength of the knee was higher in BB homozygotic men than in the Bb/bb group. No significant association was found with TaqI and FokI haplotypes. There was no significant association between muscle mass and strength, or between muscle mass and VDR genotype. Conclusion: Our data suggest that VDR gene BsmI polymorphism is associated with muscular strength in elderly men. (Aging Clin Exp Res 2010; 22: 198-205) (C) 2010, Editrice Kurti