The Experts below are selected from a list of 14988 Experts worldwide ranked by ideXlab platform
Kate G R Quinlan - One of the best experts on this subject based on the ideXlab platform.
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how does α Actinin 3 deficiency alter muscle function mechanistic insights into actn3 the gene for speed
Biochimica et Biophysica Acta, 2016Co-Authors: Peter J Houweling, Kathryn N North, Kate G R QuinlanAbstract:Abstract An estimated 1.5 billion people worldwide are deficient in the skeletal muscle protein α-Actinin-3 due to homozygosity for the common ACTN3 R577X polymorphism. α-Actinin-3 deficiency influences muscle performance in elite athletes and the general population. The sarcomeric α-Actinins were originally characterised as scaffold proteins at the muscle Z-line. Through studying the Actn3 knockout mouse and α-Actinin-3 deficient humans, significant progress has been made in understanding how ACTN3 genotype alters muscle function, leading to an appreciation of the diverse roles that α-Actinins play in muscle. The α-Actinins interact with a number of partner proteins, which broadly fall into three biological pathways—structural, metabolic and signalling. Differences in functioning of these pathways have been identified in α-Actinin-3 deficient muscle that together contributes to altered muscle performance in mice and humans. Here we discuss new insights that have been made in understanding the molecular mechanisms that underlie the consequences of α-Actinin-3 deficiency.
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actn3 genotype influences muscle performance through the regulation of calcineurin signaling
Journal of Clinical Investigation, 2013Co-Authors: Jane T Seto, Peter J Houweling, Kate G R Quinlan, Daniel G. Macarthur, Fleur Garton, Xi Fiona Zheng, Marshall W Hogarth, Paul Gregorevic, Nigel TurnerAbstract:α-Actinin-3 deficiency occurs in approximately 16% of the global population due to homozygosity for a common nonsense polymorphism in the ACTN3 gene. Loss of α-Actinin-3 is associated with reduced power and enhanced endurance capacity in elite athletes and nonathletes due to “slowing” of the metabolic and physiological properties of fast fibers. Here, we have shown that α-Actinin-3 deficiency results in increased calcineurin activity in mouse and human skeletal muscle and enhanced adaptive response to endurance training. α-Actinin-2, which is differentially expressed in α-Actinin-3–deficient muscle, has higher binding affinity for calsarcin-2, a key inhibitor of calcineurin activation. We have further demonstrated that α-Actinin-2 competes with calcineurin for binding to calsarcin-2, resulting in enhanced calcineurin signaling and reprogramming of the metabolic phenotype of fast muscle fibers. Our data provide a mechanistic explanation for the effects of the ACTN3 genotype on skeletal muscle performance in elite athletes and on adaptation to changing physical demands in the general population. In addition, we have demonstrated that the sarcomeric α-Actinins play a role in the regulation of calcineurin signaling.
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deficiency of α Actinin 3 is associated with increased susceptibility to contraction induced damage and skeletal muscle remodeling
Human Molecular Genetics, 2011Co-Authors: Peter J Houweling, Kate G R Quinlan, Jane T Seto, Monkol Lek, Xi F Zheng, Fleur GartonAbstract:Sarcomeric α-Actinins (α-Actinin-2 and -3) are a major component of the Z-disk in skeletal muscle, where they crosslink actin and other structural proteins to maintain an ordered myofibrillar array. Homozygosity for the common null polymorphism (R577X) in ACTN3 results in the absence of fast fiber-specific α-Actinin-3 in ∼20% of the general population. α-Actinin-3 deficiency is associated with decreased force generation and is detrimental to sprint and power performance in elite athletes, suggesting that α-Actinin-3 is necessary for optimal forceful repetitive muscle contractions. Since Z-disks are the structures most vulnerable to eccentric damage, we sought to examine the effects of α-Actinin-3 deficiency on sarcomeric integrity. Actn3 knockout mouse muscle showed significantly increased force deficits following eccentric contraction at 30% stretch, suggesting that α-Actinin-3 deficiency results in an increased susceptibility to muscle damage at the extremes of muscle performance. Microarray analyses demonstrated an increase in muscle remodeling genes, which we confirmed at the protein level. The loss of α-Actinin-3 and up-regulation of α-Actinin-2 resulted in no significant changes to the total pool of sarcomeric α-Actinins, suggesting that alterations in fast fiber Z-disk properties may be related to differences in functional protein interactions between α-Actinin-2 and α-Actinin-3. In support of this, we demonstrated that the Z-disk proteins, ZASP, titin and vinculin preferentially bind to α-Actinin-2. Thus, the loss of α-Actinin-3 changes the overall protein composition of fast fiber Z-disks and alters their elastic properties, providing a mechanistic explanation for the loss of force generation and increased susceptibility to eccentric damage in α-Actinin-3-deficient individuals.
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α Actinin 3 deficiency results in reduced glycogen phosphorylase activity and altered calcium handling in skeletal muscle
Human Molecular Genetics, 2010Co-Authors: Kate G R Quinlan, Daniel G. Macarthur, Jane T Seto, Nigel Turner, Aurelie Vandebrouck, Matthias Floetenmeyer, Joanna M RafteryAbstract:Approximately one billion people worldwide are homozygous for a stop codon polymorphism in the ACTN3 gene (R577X) which results in complete deficiency of the fast fibre muscle protein a-Actinin-3. ACTN3 genotype is associated with human athletic performance and a-Actinin-3 deficient mice [Actn3 knockout (KO) mice] have a shift in the properties of fast muscle fibres towards slower fibre properties, with increased activity of multiple enzymes in the aerobic metabolic pathway and slower contractile properties. a-Actinins have been shown to interact with a number of muscle proteins including the key metabolic regulator glycogen phosphorylase (GPh). In this study, we demonstrated a link between a-Actinin-3 and glycogen metabolism which may underlie the metabolic changes seen in the KO mouse. Actn3 KO mice have higher muscle glycogen content and a 50% reduction in the activity of GPh. The reduction in enzyme activity is accompanied by altered post-translational modification of GPh, suggesting that a-Actinin-3 regulates GPh activity by altering its level of phosphorylation. We propose that the changes in glycogen metabolism underlie the downstream metabolic consequences of a-Actinin-3 deficiency. Finally, as GPh has been shown to regulate calcium handling, we examined calcium handling in KO mouse primary mouse myoblasts and find changes that may explain the slower contractile properties previously observed in these mice. We propose that the alteration in GPh activity in the absence of a-Actinin-3 is a fundamental mechanistic link in the association between ACTN3 genotype and human performance.
Kathryn N North - One of the best experts on this subject based on the ideXlab platform.
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how does α Actinin 3 deficiency alter muscle function mechanistic insights into actn3 the gene for speed
Biochimica et Biophysica Acta, 2016Co-Authors: Peter J Houweling, Kathryn N North, Kate G R QuinlanAbstract:Abstract An estimated 1.5 billion people worldwide are deficient in the skeletal muscle protein α-Actinin-3 due to homozygosity for the common ACTN3 R577X polymorphism. α-Actinin-3 deficiency influences muscle performance in elite athletes and the general population. The sarcomeric α-Actinins were originally characterised as scaffold proteins at the muscle Z-line. Through studying the Actn3 knockout mouse and α-Actinin-3 deficient humans, significant progress has been made in understanding how ACTN3 genotype alters muscle function, leading to an appreciation of the diverse roles that α-Actinins play in muscle. The α-Actinins interact with a number of partner proteins, which broadly fall into three biological pathways—structural, metabolic and signalling. Differences in functioning of these pathways have been identified in α-Actinin-3 deficient muscle that together contributes to altered muscle performance in mice and humans. Here we discuss new insights that have been made in understanding the molecular mechanisms that underlie the consequences of α-Actinin-3 deficiency.
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sequence analysis of the equine actn3 gene in australian horse breeds
Gene, 2014Co-Authors: Kristen C Thomas, N A Hamilton, Peter J Houweling, Kathryn N NorthAbstract:Abstract The sarcomeric α-Actinins, encoded by the genes ACTN2 and ACTN3, are major structural components of the Z-line and have high sequence similarity. α-Actinin-2 is present in all skeletal muscle fibres, while α-Actinin-3 has developed specialized expression in only type 2 (fast, glycolytic) fibres. A common single nucleotide polymorphism (SNP) in the human ACTN3 gene (R577X) has been found to influence muscle performance in elite athletes and the normal population. For this reason, equine ACTN3 (eACTN3) is considered to be a possible candidate that may influence horse performance. In this study, the intron/exon boundaries and entire coding region of eACTN3 have been sequenced in five Australian horse breeds (Thoroughbred, Arabian, Standardbred, Clydsdale and Shire) and compared to the eACTN3 GenBank sequence. A total of 34 SNPs were identified, of which 26 were intronic and eight exonic. All exonic SNPs were synonymous; however, five intronic SNPs showed significant differences between breeds. A total of 72 horses were genotyped for a SNP located in the promoter region of the eACTN3 gene (g. 1104 G > A) which differed significantly between breed groups. We hypothesize that this polymorphism influences eACTN3 expression and with further studies may provide a novel marker of horse performance in the future.
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Sarcomeric α-Actinins and their role in human muscle disease
Future Neurology, 2009Co-Authors: Peter J Houweling, Kathryn N NorthAbstract:In skeletal muscle, the sarcomeric α-Actinins (α-Actinin-2 and -3) are a major component of the Z-line and crosslink actin thin filaments to maintain the structure of the sarcomere. Based on their known protein binding partners, the sarcomeric α-Actinins are likely to have a number of structural, signaling and metabolic roles in skeletal muscle. In addition, the α-Actinins interact with many proteins responsible for inherited muscle disorders. In this paper, we explore the role of the sarcomeric α-Actinins in normal skeletal muscle and in the pathogenesis of a range of neuromuscular disorders.
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a gene for speed the evolution and function of α Actinin 3
BioEssays, 2004Co-Authors: Daniel G. Macarthur, Kathryn N NorthAbstract:The alpha-Actinins are an ancient family of actin-binding proteins that play structural and regulatory roles in cytoskeletal organisation and muscle contraction. alpha-Actinin-3 is the most-highly specialised of the four mammalian alpha-Actinins, with its expression restricted largely to fast glycolytic fibres in skeletal muscle. Intriguingly, a significant proportion ( approximately 18%) of the human population is totally deficient in alpha-Actinin-3 due to homozygosity for a premature stop codon polymorphism (R577X) in the ACTN3 gene. Recent work in our laboratory has revealed a strong association between R577X genotype and performance in a variety of athletic endeavours. We are currently exploring the function and evolutionary history of the ACTN3 gene and other alpha-Actinin family members. The alpha-Actinin family provides a fascinating case study in molecular evolution, illustrating phenomena such as functional redundancy in duplicate genes, the evolution of protein function, and the action of natural selection during recent human evolution.
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A gene for speed? The evolution and function of α‐Actinin‐3
BioEssays : news and reviews in molecular cellular and developmental biology, 2004Co-Authors: Daniel G. Macarthur, Kathryn N NorthAbstract:The alpha-Actinins are an ancient family of actin-binding proteins that play structural and regulatory roles in cytoskeletal organisation and muscle contraction. alpha-Actinin-3 is the most-highly specialised of the four mammalian alpha-Actinins, with its expression restricted largely to fast glycolytic fibres in skeletal muscle. Intriguingly, a significant proportion ( approximately 18%) of the human population is totally deficient in alpha-Actinin-3 due to homozygosity for a premature stop codon polymorphism (R577X) in the ACTN3 gene. Recent work in our laboratory has revealed a strong association between R577X genotype and performance in a variety of athletic endeavours. We are currently exploring the function and evolutionary history of the ACTN3 gene and other alpha-Actinin family members. The alpha-Actinin family provides a fascinating case study in molecular evolution, illustrating phenomena such as functional redundancy in duplicate genes, the evolution of protein function, and the action of natural selection during recent human evolution.
Peter J Houweling - One of the best experts on this subject based on the ideXlab platform.
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how does α Actinin 3 deficiency alter muscle function mechanistic insights into actn3 the gene for speed
Biochimica et Biophysica Acta, 2016Co-Authors: Peter J Houweling, Kathryn N North, Kate G R QuinlanAbstract:Abstract An estimated 1.5 billion people worldwide are deficient in the skeletal muscle protein α-Actinin-3 due to homozygosity for the common ACTN3 R577X polymorphism. α-Actinin-3 deficiency influences muscle performance in elite athletes and the general population. The sarcomeric α-Actinins were originally characterised as scaffold proteins at the muscle Z-line. Through studying the Actn3 knockout mouse and α-Actinin-3 deficient humans, significant progress has been made in understanding how ACTN3 genotype alters muscle function, leading to an appreciation of the diverse roles that α-Actinins play in muscle. The α-Actinins interact with a number of partner proteins, which broadly fall into three biological pathways—structural, metabolic and signalling. Differences in functioning of these pathways have been identified in α-Actinin-3 deficient muscle that together contributes to altered muscle performance in mice and humans. Here we discuss new insights that have been made in understanding the molecular mechanisms that underlie the consequences of α-Actinin-3 deficiency.
-
sequence analysis of the equine actn3 gene in australian horse breeds
Gene, 2014Co-Authors: Kristen C Thomas, N A Hamilton, Peter J Houweling, Kathryn N NorthAbstract:Abstract The sarcomeric α-Actinins, encoded by the genes ACTN2 and ACTN3, are major structural components of the Z-line and have high sequence similarity. α-Actinin-2 is present in all skeletal muscle fibres, while α-Actinin-3 has developed specialized expression in only type 2 (fast, glycolytic) fibres. A common single nucleotide polymorphism (SNP) in the human ACTN3 gene (R577X) has been found to influence muscle performance in elite athletes and the normal population. For this reason, equine ACTN3 (eACTN3) is considered to be a possible candidate that may influence horse performance. In this study, the intron/exon boundaries and entire coding region of eACTN3 have been sequenced in five Australian horse breeds (Thoroughbred, Arabian, Standardbred, Clydsdale and Shire) and compared to the eACTN3 GenBank sequence. A total of 34 SNPs were identified, of which 26 were intronic and eight exonic. All exonic SNPs were synonymous; however, five intronic SNPs showed significant differences between breeds. A total of 72 horses were genotyped for a SNP located in the promoter region of the eACTN3 gene (g. 1104 G > A) which differed significantly between breed groups. We hypothesize that this polymorphism influences eACTN3 expression and with further studies may provide a novel marker of horse performance in the future.
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actn3 genotype influences muscle performance through the regulation of calcineurin signaling
Journal of Clinical Investigation, 2013Co-Authors: Jane T Seto, Peter J Houweling, Kate G R Quinlan, Daniel G. Macarthur, Fleur Garton, Xi Fiona Zheng, Marshall W Hogarth, Paul Gregorevic, Nigel TurnerAbstract:α-Actinin-3 deficiency occurs in approximately 16% of the global population due to homozygosity for a common nonsense polymorphism in the ACTN3 gene. Loss of α-Actinin-3 is associated with reduced power and enhanced endurance capacity in elite athletes and nonathletes due to “slowing” of the metabolic and physiological properties of fast fibers. Here, we have shown that α-Actinin-3 deficiency results in increased calcineurin activity in mouse and human skeletal muscle and enhanced adaptive response to endurance training. α-Actinin-2, which is differentially expressed in α-Actinin-3–deficient muscle, has higher binding affinity for calsarcin-2, a key inhibitor of calcineurin activation. We have further demonstrated that α-Actinin-2 competes with calcineurin for binding to calsarcin-2, resulting in enhanced calcineurin signaling and reprogramming of the metabolic phenotype of fast muscle fibers. Our data provide a mechanistic explanation for the effects of the ACTN3 genotype on skeletal muscle performance in elite athletes and on adaptation to changing physical demands in the general population. In addition, we have demonstrated that the sarcomeric α-Actinins play a role in the regulation of calcineurin signaling.
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deficiency of α Actinin 3 is associated with increased susceptibility to contraction induced damage and skeletal muscle remodeling
Human Molecular Genetics, 2011Co-Authors: Peter J Houweling, Kate G R Quinlan, Jane T Seto, Monkol Lek, Xi F Zheng, Fleur GartonAbstract:Sarcomeric α-Actinins (α-Actinin-2 and -3) are a major component of the Z-disk in skeletal muscle, where they crosslink actin and other structural proteins to maintain an ordered myofibrillar array. Homozygosity for the common null polymorphism (R577X) in ACTN3 results in the absence of fast fiber-specific α-Actinin-3 in ∼20% of the general population. α-Actinin-3 deficiency is associated with decreased force generation and is detrimental to sprint and power performance in elite athletes, suggesting that α-Actinin-3 is necessary for optimal forceful repetitive muscle contractions. Since Z-disks are the structures most vulnerable to eccentric damage, we sought to examine the effects of α-Actinin-3 deficiency on sarcomeric integrity. Actn3 knockout mouse muscle showed significantly increased force deficits following eccentric contraction at 30% stretch, suggesting that α-Actinin-3 deficiency results in an increased susceptibility to muscle damage at the extremes of muscle performance. Microarray analyses demonstrated an increase in muscle remodeling genes, which we confirmed at the protein level. The loss of α-Actinin-3 and up-regulation of α-Actinin-2 resulted in no significant changes to the total pool of sarcomeric α-Actinins, suggesting that alterations in fast fiber Z-disk properties may be related to differences in functional protein interactions between α-Actinin-2 and α-Actinin-3. In support of this, we demonstrated that the Z-disk proteins, ZASP, titin and vinculin preferentially bind to α-Actinin-2. Thus, the loss of α-Actinin-3 changes the overall protein composition of fast fiber Z-disks and alters their elastic properties, providing a mechanistic explanation for the loss of force generation and increased susceptibility to eccentric damage in α-Actinin-3-deficient individuals.
-
Sarcomeric α-Actinins and their role in human muscle disease
Future Neurology, 2009Co-Authors: Peter J Houweling, Kathryn N NorthAbstract:In skeletal muscle, the sarcomeric α-Actinins (α-Actinin-2 and -3) are a major component of the Z-line and crosslink actin thin filaments to maintain the structure of the sarcomere. Based on their known protein binding partners, the sarcomeric α-Actinins are likely to have a number of structural, signaling and metabolic roles in skeletal muscle. In addition, the α-Actinins interact with many proteins responsible for inherited muscle disorders. In this paper, we explore the role of the sarcomeric α-Actinins in normal skeletal muscle and in the pathogenesis of a range of neuromuscular disorders.
Jane T Seto - One of the best experts on this subject based on the ideXlab platform.
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actn3 genotype influences muscle performance through the regulation of calcineurin signaling
Journal of Clinical Investigation, 2013Co-Authors: Jane T Seto, Peter J Houweling, Kate G R Quinlan, Daniel G. Macarthur, Fleur Garton, Xi Fiona Zheng, Marshall W Hogarth, Paul Gregorevic, Nigel TurnerAbstract:α-Actinin-3 deficiency occurs in approximately 16% of the global population due to homozygosity for a common nonsense polymorphism in the ACTN3 gene. Loss of α-Actinin-3 is associated with reduced power and enhanced endurance capacity in elite athletes and nonathletes due to “slowing” of the metabolic and physiological properties of fast fibers. Here, we have shown that α-Actinin-3 deficiency results in increased calcineurin activity in mouse and human skeletal muscle and enhanced adaptive response to endurance training. α-Actinin-2, which is differentially expressed in α-Actinin-3–deficient muscle, has higher binding affinity for calsarcin-2, a key inhibitor of calcineurin activation. We have further demonstrated that α-Actinin-2 competes with calcineurin for binding to calsarcin-2, resulting in enhanced calcineurin signaling and reprogramming of the metabolic phenotype of fast muscle fibers. Our data provide a mechanistic explanation for the effects of the ACTN3 genotype on skeletal muscle performance in elite athletes and on adaptation to changing physical demands in the general population. In addition, we have demonstrated that the sarcomeric α-Actinins play a role in the regulation of calcineurin signaling.
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deficiency of α Actinin 3 is associated with increased susceptibility to contraction induced damage and skeletal muscle remodeling
Human Molecular Genetics, 2011Co-Authors: Peter J Houweling, Kate G R Quinlan, Jane T Seto, Monkol Lek, Xi F Zheng, Fleur GartonAbstract:Sarcomeric α-Actinins (α-Actinin-2 and -3) are a major component of the Z-disk in skeletal muscle, where they crosslink actin and other structural proteins to maintain an ordered myofibrillar array. Homozygosity for the common null polymorphism (R577X) in ACTN3 results in the absence of fast fiber-specific α-Actinin-3 in ∼20% of the general population. α-Actinin-3 deficiency is associated with decreased force generation and is detrimental to sprint and power performance in elite athletes, suggesting that α-Actinin-3 is necessary for optimal forceful repetitive muscle contractions. Since Z-disks are the structures most vulnerable to eccentric damage, we sought to examine the effects of α-Actinin-3 deficiency on sarcomeric integrity. Actn3 knockout mouse muscle showed significantly increased force deficits following eccentric contraction at 30% stretch, suggesting that α-Actinin-3 deficiency results in an increased susceptibility to muscle damage at the extremes of muscle performance. Microarray analyses demonstrated an increase in muscle remodeling genes, which we confirmed at the protein level. The loss of α-Actinin-3 and up-regulation of α-Actinin-2 resulted in no significant changes to the total pool of sarcomeric α-Actinins, suggesting that alterations in fast fiber Z-disk properties may be related to differences in functional protein interactions between α-Actinin-2 and α-Actinin-3. In support of this, we demonstrated that the Z-disk proteins, ZASP, titin and vinculin preferentially bind to α-Actinin-2. Thus, the loss of α-Actinin-3 changes the overall protein composition of fast fiber Z-disks and alters their elastic properties, providing a mechanistic explanation for the loss of force generation and increased susceptibility to eccentric damage in α-Actinin-3-deficient individuals.
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α Actinin 3 deficiency results in reduced glycogen phosphorylase activity and altered calcium handling in skeletal muscle
Human Molecular Genetics, 2010Co-Authors: Kate G R Quinlan, Daniel G. Macarthur, Jane T Seto, Nigel Turner, Aurelie Vandebrouck, Matthias Floetenmeyer, Joanna M RafteryAbstract:Approximately one billion people worldwide are homozygous for a stop codon polymorphism in the ACTN3 gene (R577X) which results in complete deficiency of the fast fibre muscle protein a-Actinin-3. ACTN3 genotype is associated with human athletic performance and a-Actinin-3 deficient mice [Actn3 knockout (KO) mice] have a shift in the properties of fast muscle fibres towards slower fibre properties, with increased activity of multiple enzymes in the aerobic metabolic pathway and slower contractile properties. a-Actinins have been shown to interact with a number of muscle proteins including the key metabolic regulator glycogen phosphorylase (GPh). In this study, we demonstrated a link between a-Actinin-3 and glycogen metabolism which may underlie the metabolic changes seen in the KO mouse. Actn3 KO mice have higher muscle glycogen content and a 50% reduction in the activity of GPh. The reduction in enzyme activity is accompanied by altered post-translational modification of GPh, suggesting that a-Actinin-3 regulates GPh activity by altering its level of phosphorylation. We propose that the changes in glycogen metabolism underlie the downstream metabolic consequences of a-Actinin-3 deficiency. Finally, as GPh has been shown to regulate calcium handling, we examined calcium handling in KO mouse primary mouse myoblasts and find changes that may explain the slower contractile properties previously observed in these mice. We propose that the alteration in GPh activity in the absence of a-Actinin-3 is a fundamental mechanistic link in the association between ACTN3 genotype and human performance.
Fleur Garton - One of the best experts on this subject based on the ideXlab platform.
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actn3 genotype influences muscle performance through the regulation of calcineurin signaling
Journal of Clinical Investigation, 2013Co-Authors: Jane T Seto, Peter J Houweling, Kate G R Quinlan, Daniel G. Macarthur, Fleur Garton, Xi Fiona Zheng, Marshall W Hogarth, Paul Gregorevic, Nigel TurnerAbstract:α-Actinin-3 deficiency occurs in approximately 16% of the global population due to homozygosity for a common nonsense polymorphism in the ACTN3 gene. Loss of α-Actinin-3 is associated with reduced power and enhanced endurance capacity in elite athletes and nonathletes due to “slowing” of the metabolic and physiological properties of fast fibers. Here, we have shown that α-Actinin-3 deficiency results in increased calcineurin activity in mouse and human skeletal muscle and enhanced adaptive response to endurance training. α-Actinin-2, which is differentially expressed in α-Actinin-3–deficient muscle, has higher binding affinity for calsarcin-2, a key inhibitor of calcineurin activation. We have further demonstrated that α-Actinin-2 competes with calcineurin for binding to calsarcin-2, resulting in enhanced calcineurin signaling and reprogramming of the metabolic phenotype of fast muscle fibers. Our data provide a mechanistic explanation for the effects of the ACTN3 genotype on skeletal muscle performance in elite athletes and on adaptation to changing physical demands in the general population. In addition, we have demonstrated that the sarcomeric α-Actinins play a role in the regulation of calcineurin signaling.
-
deficiency of α Actinin 3 is associated with increased susceptibility to contraction induced damage and skeletal muscle remodeling
Human Molecular Genetics, 2011Co-Authors: Peter J Houweling, Kate G R Quinlan, Jane T Seto, Monkol Lek, Xi F Zheng, Fleur GartonAbstract:Sarcomeric α-Actinins (α-Actinin-2 and -3) are a major component of the Z-disk in skeletal muscle, where they crosslink actin and other structural proteins to maintain an ordered myofibrillar array. Homozygosity for the common null polymorphism (R577X) in ACTN3 results in the absence of fast fiber-specific α-Actinin-3 in ∼20% of the general population. α-Actinin-3 deficiency is associated with decreased force generation and is detrimental to sprint and power performance in elite athletes, suggesting that α-Actinin-3 is necessary for optimal forceful repetitive muscle contractions. Since Z-disks are the structures most vulnerable to eccentric damage, we sought to examine the effects of α-Actinin-3 deficiency on sarcomeric integrity. Actn3 knockout mouse muscle showed significantly increased force deficits following eccentric contraction at 30% stretch, suggesting that α-Actinin-3 deficiency results in an increased susceptibility to muscle damage at the extremes of muscle performance. Microarray analyses demonstrated an increase in muscle remodeling genes, which we confirmed at the protein level. The loss of α-Actinin-3 and up-regulation of α-Actinin-2 resulted in no significant changes to the total pool of sarcomeric α-Actinins, suggesting that alterations in fast fiber Z-disk properties may be related to differences in functional protein interactions between α-Actinin-2 and α-Actinin-3. In support of this, we demonstrated that the Z-disk proteins, ZASP, titin and vinculin preferentially bind to α-Actinin-2. Thus, the loss of α-Actinin-3 changes the overall protein composition of fast fiber Z-disks and alters their elastic properties, providing a mechanistic explanation for the loss of force generation and increased susceptibility to eccentric damage in α-Actinin-3-deficient individuals.
