A common polymorphism (R577X) in the ACTN3 gene results in complete deficiency of α-actinin-3 protein in ∼16% of humans worldwide. The presence of α-actinin-3 protein is associated with improved sprint/power performance in athletes and the general population. Despite this, there is evidence that the null genotype XX has been acted on by recent positive selection, likely due to its emerging role in the regulation of muscle metabolism. α-Actinin-3 deficiency reduces the activity of glycogen phosphorylase and results in a fundamental shift toward more oxidative pathways of energy utilization.
Deficiency of the fast-fiber skeletal muscle protein α-actinin-3 is common in the general population due to a polymorphic-null allele in the ACTN3 gene. Numerous independent studies have established that the absence of α-actinin-3 is detrimental to sprint and power performance in athletes and in the general population (1, 25, 55, 63, 66). The sarcomeric α-actinins have long been considered to be primarily structural proteins. However, recent data suggest that α-actinin-3 plays a significant role in the regulation of muscle metabolism. α-Actinin-3 deficiency results in a shift in the characteristics of fast glycolytic muscle fibers toward those of slow muscle fibers with oxidative metabolism (48, 49, 62). This review examines the emerging role of α-actinin-3 in regulation of skeletal muscle metabolism.
The α-Actinin Family of Proteins
The α-actinins are a family of actin-binding proteins that have been identified in a diverse range of organisms, suggesting an ancient origin (3, 8, 33, 50). The α-actinin protein structure is comprised of three domains; an NH2-terminal actin-binding domain, a central rod domain containing four internal repeated 122-amino acid motifs, and a COOH-terminal region containing two EF-hand calcium binding motifs. The four repetitive motifs found in α-actinin share homology with spectrin, suggesting a common evolutionary origin of the α-actinin proteins and the spectrin family of actin binding cytoskeletal proteins, of which dystrophin is a member (13, 75). There is marked evolutionary conservation of the α-actinin genes across species, particularly within the NH2-terminal actin-binding domain (9).
There are four α-actinin genes in humans, ACTN1–ACTN4 (9, 85). ACTN1 and ACTN4 contain functional calcium-sensitive EF hands, whereas the skeletal muscle or sarcomeric α-actinins, encoded by ACTN2 and ACTN3, have EF hands that are not calcium sensitive (15). In humans, α-actinin-2 is expressed in the heart, in all skeletal muscle fibers, and in the brain, whereas α-actinin-3 is expressed only in fast glycolytic skeletal muscle fibers, is not present in cardiac muscle, and has low levels of expression in the brain (50). These two proteins diverged from one another following a gene duplication event over 300 million years ago (mya), but have retained considerable sequence similarity (43). Human α-actinin-2 and α-actinin-3 are 79% identical and 91% similar at the amino acid level (9, 42).
The sarcomeres are repeating units that constitute the contractile apparatus of the muscle fiber (myofibril) and are comprised of actin-containing thin filaments and thick filaments containing myosin (19). The thin filaments are anchored to electron-dense bands known as Z-lines, in perpendicular orientation to the myofibrils. The ordered alignment of the Z-lines in adjacent myofibrils enables co-coordinated contractions between myofibrils and allows transmission of contractions to the costameres at which the Z-line is linked to the muscle membrane. The sarcomeric α-actinins are major components of the Z-line and historically have been thought to have a primarily structural role in skeletal muscle (10, 11). In addition to actin, they bind to many of the Z-line-associated proteins including myotilin, myopalladin, Z-band alternatively spliced PDZ motif protein (ZASP), filamin-, actinin-, and telethonin-binding protein of the Z-disc (FATZ), and titin (1, 5, 7, 27, 28, 40, 65). The α-actinins can form antiparallel dimers with themselves or other α-actinins, allowing cross linking of actin and titin filaments from neighboring sarcomeres and are thought to play a significant role in maintenance of the structural integrity of the Z-line of skeletal muscle (9–11, 16, 47, 70).
α-Actinin-3 Deficiency is Common in the General Population
In 1999, we described a common single-base transversion (C→T) in exon 16 of the ACTN3 gene that converts an arginine residue (R) to a stop codon (X) at amino acid position 577 (56). Approximately 16% of the world population is completely deficient in α-actinin-3 protein due to homozygosity for the R577X stop codon (ACTN3 577XX genotype) (48). There is variation in frequency of the R577X allele in different ethnic groups, with allele frequencies of 0.55 in Europeans, 0.52 in Asian populations, and 0.09 in Africans (49). α-Actinin-3 deficiency does not result in muscle disease, suggesting that it is not essential for baseline muscle function, and that the closely related isoform, α-actinin-2, can at least partially compensate for its absence at the Z-line in fast muscle fibers. However, ACTN3 has been highly conserved during vertebrate evolution, suggesting that the sarcomeric α-actinins are not completely functionally redundant and that ACTN3 has evolved to perform specific functions in fast fibers (47, 50).
We have studied genetic variation around the ACTN3 R577X polymorphism across a wide range of populations using DNA available through the International HapMap project (48). Low levels of genetic variation and an unusually long region of complete homozygosity in the region surrounding the 577X allele suggest a recent and rapid expansion in the frequency of this allele amongst Eurasian population due to positive selection. Thus, although ACTN3 appears have been conserved through early evolution(∼300 mya), there is now recent positive selection (∼15–33 thousand years ago) favoring the nonfunctional ACTN3 allele. This suggests that both states, α-actinin-3 deficiency and α-actinin-3 expression, may confer benefits to muscle function that have been acted on through natural selection.
α-Actinin-3 Deficiency Improves Human Sprint Performance
In 2003 in collaboration with the Australian Institute of Sport, we showed that ACTN3 genotype is strongly associated with elite athlete status (83). There is a striking and highly significant reduction in the frequency of α-actinin-3-deficient individuals among sprint/power athletes compared with controls (FIGURE 1). The association between the ACTN3 genotype and sprint performance has been replicated in a number of studies in populations of varied ethnicity, including European, American, and Israeli athletes (1, 25, 55, 63, 66). A meta-analysis of existing published data has given a P value of <0.5 × 1011 of the effect of ACTN3 genotype on sprint performance (46). Although α-actinin-3 deficiency is associated with poorer muscle strength and sprint performance, loss of α-actinin-3 appears to be beneficial in certain circumstances, with the frequency of the XX-null genotype higher in endurance athletes than in controls in some studies (26, 83).
Similar ACTN3 genotype associations have also been demonstrated in nonathletes, with deficiency of α-actinin-3 associated with significantly slower 40-m sprint times in Greek adolescent males (51), lower isometric maximal voluntary muscle contractions (20), and lower knee extensor shortening and lengthening peak torques in untrained adult women and men (20, 51, 77, 78). In summary, the large number of human studies that have been performed to date show that the ACTN3 R577X polymorphism represents an important genetic factor associated with variations in muscle performance in humans, with the presence of α-actinin-3 associated with improved sprint and power performance.
Understanding the Role of α-Actinin-3 in Muscle Performance: The Actn3 KO Mouse
To better understand the mechanisms underlying the effect of α-actinin-3 on skeletal muscle performance and the factors that might contribute toward positive selection for the X allele during recent human evolution, we generated a knockout mouse (Actn3KO) completely deficient for α-actinin-3 at the protein and mRNA level (49). Similar to humans, wild-type (WT) mice express α-actinin-3 predominantly in fast fibers. Unlike humans, α-actinin-2 is usually expressed predominantly in type 1 and type IIa fibers in postnatal mouse muscle. In the Actn3 KO, α-actinin-2 is upregulated and expressed in all fibers, mimicking the pattern of expression seen in ACTN3 577XX humans. Like humans, α-actinin-3 deficiency in the Actn3 KO mouse does not result in overt muscle disease. The Actn3 KO mice appear normal and have similar activity levels to WT mice on open-field testing (49).
α-Actinin-3 Deficiency Reduces Muscle Mass
Actn3 KO mice weigh slightly less than WT mice, with lower muscle mass seen in all muscles normally expressing α-actinin-3 (48). The heart and slow-twitch soleus muscle (located in the lower hindlimb underlying the gastrocnemius) do not normally express α-actinin-3 and so provide an internal negative control. There was no difference in the size of the heart between WT and Actn3 KO mice. Unlike the other muscles analyzed, we saw a trend toward an increase in size in the soleus. This may reflect hypertrophy of the soleus to compensate for reduced strength in the surrounding muscles. The increase in size of the soleus also argues against an overall “runt” effect among the Actn3 KOs. Rather, it suggests that the reduction in muscle mass in the presence of α-actinin-3 deficiency is specific to the muscles in which it is normally expressed. As further evidence of a role for α-actinin-3 in muscle size, α-actinin-3 deficiency has also been associated with reduced muscle mass in Japanese and American women (24, 77, 78, 86).
The reduction in muscle mass that we see in the Actn3KO appears to be due to a reduced diameter of the type 2B, fast glycolytic fibers that normally express α-actinin-3. We see no change in the number of muscle fibers or significant alteration in fiber type as defined by myosin heavy chain isoform. Rather, we see that the type 2B muscle fibers have a cross-sectional area that is 34% smaller than the 2B fibers found in WT littermates. Similarly, actinin-3 deficiency has been shown to reduce the total muscle cross-sectional area occupied by fast, glycolytic (type 2X) fibers in ACTN3 577XX humans (77).
α-Actinin-3 Deficiency Reduces Muscle Strength
Grip strength is significantly lower in Actn3 KO mice (6–7%) compared with WT mice, although still within the normal range overall (48). This confirms that the Actn3KO mice are modeling normal variation rather than weakness as a manifestation of muscle disease (FIGURE 1). Human studies have also shown reduced muscle strength in XX individuals. In a group of elite male road cyclists (n = 46), individuals with XX-genotypes were found to have less peak power output and less power to tolerate high submaximal workloads compared with RR genotypes (35). Reduced peak torque values were also seen among XX women in a large cohort of women across a broad span of age range (848 women aged 22–90 yr) (78).
α-Actinin-3 Deficiency Results in Improved Endurance Capacity
Intriguingly, we found that Actn3 KO mice have an increased capacity to run longer distances (FIGURE 1) (49). Using a modified intrinsic exercise test where mice are run to exhaustion, Actn3 KO mice were able to run on average 33% further than WT mice. This data is consistent with the findings of our original human association study in which we found a trend toward an increase in the frequency of XX individuals among endurance athletes, reaching significance among female athletes. This association was also significant when road cycling athletes were analyzed separately and in a study of Israeli elite athletes (26, 83). However, other studies have not replicated the association between ACTN3 genotype and elite endurance performance. This suggests that the association between α-actinin-3 deficiency and endurance is not as strong as its association with reduced performance in sprint and power activities (2, 45, 53, 55, 59, 67, 84).
It is interesting to speculate why it is that improved endurance is apparent in our Actn3 KO mice, when some human studies have not demonstrated a significant effect in XX individuals. Not surprisingly, there are significant differences in muscle metabolism and contractile properties between mice and humans. Mice have a greater disparity in metabolism between slow and fast muscle fiber types. In particular, fast fibers in mice display a greater shift toward glycolytic metabolism than humans, and mouse muscle has a much higher proporation of fast, glycolytic fibers (1). Therefore, in addition to overcoming and environmental and genetic variability inherent in human studies, the effect of α-actinin-3 on glycolytic muscle metabolism may also be magnified in the mouse model.
α-Actinin-3 Deficiency Results in Increased Activity of Mitochondrial Enzymes
The most striking phenotype in the Actn3 KO mouse is a metabolic shift in the characteristics of fast muscle fibers toward those of slow oxidative fibers (48). At a histochemical level, there is increased intensity for a number of mitochondrial-associated enzyme stains in KO mouse muscle; NADH-tetrazolium reductase (a reductase that is present in both mitochondria and the sarcoplasmic reticulum) and succinate dehydrogenase (SDH), which is associated with the tricarboxylic acid cycle (49). Immunoblotting also shows increased levels of porin (found in the outer mitochondrial membrane), and cytochrome c oxidase (CCO), one of the rate-limiting steps of oxidative phosphorylation in the mitochondria. At an enzyme level, CCO shows activity levels that are 25–39% higher in Actn3 KO mouse muscle compared with WT (FIGURE 2).
In addition to SDH, another key pacemaking enzyme in the tricarboxylic acid (TCA) cycle, citrate synthase is also elevated in the Actn3KO48. The TCA cycle lies at the hub of energy pathways for utilization of carbohydrates, fats, and proteins. Once glucose has been converted to pyruvate by the process of glycolysis, it can pass into the mitochondria where it is converted into acetyl-CoA by decarboxylation and can enter the TCA cycle. The TCA cycle does not utilize oxygen directly, so it depends on subsequent passage through oxidative phosphorylation.
The activity of two mitochondrial enzymes involved in fatty acid oxidation, (hydroxyacyl-CoA dehydrogenase and medium chain acyl-CoA dehydrogenase) are elevated in the Actn3 KO mouse (48). For fat to be metabolized, triglycerides are hydrolyzed to fatty acids and glycerol. Fatty acids can be broken down through beta oxidation and may then be delivered to the TCA cycle as acetyl CoA or succinyl CoA. At a functional level, the Actn3KO mouse has an increased capacity to oxidize fats (palmitate oxidation; Quinlan K, unpublished observations).
Quantification of mitochondrial DNA copy number is unaltered in Actn3 KO mouse muscle (48), suggesting that the increase in activity of enzymes located in the mitcohondria is due to increased mitochondrial activity rather than increased mitochondrial number. Consistent with this, there is no increase in another mitochondrial enzyme, glutamate dehydrogenase, which is involved in nitrogen and glutamate metabolism, in the Actn3 KO mouse. In addition, the levels of PGC1α, a known marker of increased mitochondrial biogenesis, are similar in WT and Actn3 KO mice.
α-Actinin-3 Deficiency Results in Increased Glycolysis
Hexokinase, the enzyme that catalyses the first step in glycolysis is significantly upregulated in the Actn3 KO mouse muscle, as is glyceraldehyde-6-phosphate dehydrogenase (GAPDH). Glycolytic metabolism is coupled to mitochondrial oxidative metabolism in the presence of oxygen but can also generate ATP in its absence. GAPDH is involved in the sixth step of glycolysis and is typically highly expressed in all tissues leading to its frequent use as a house-keeping control gene for Western blotting and RT-PCR. Interestingly, we saw no detectable change in the activity of phosphofructokinase, a key regulatory and rate-limiting step in glycolysis.
Despite the striking differences we see in muscle metabolism properties we see in Actn3KO muscle, we have not seen changes in muscle fiber-type proportions, suggesting that the shift in metabolism in the Actn3KO is not due to an increased proportion of oxidative, type 1, or type 2A fibers.
α-Actinin-3 Deficiency Results in Increased Glycogen Content in Muscle
Using three methods [periodic acid-Schiff (PAS) staining, glycogen assays, and dual-axis electron microscopic tomography], we have demonstrated that muscle glycogen content is significantly increased in Actn3 KO mice (62). By microscopic tomography, glycogen volume as a percentage of the cytoplasmic volume was 1.9% in Actn3 KO mice compared with 1.0% in WT. In ACTN3 577XX humans, there is also an increase in glycogen compared with 577RR and 577RX individuals, who express α-actinin-3.
Glycogen metabolism is the key pathway for energy production during high-intensity activity, and depletion of glycogen results in muscle fatigue. Glycogen metabolism is controlled by complex feedback mechanisms (38). Glycogen synthesis is controlled by the delivery of glucose to the cell (glucose transport) and the enzyme glycogen synthase. Glycogen utilization (glycogenolysis) is catalyzed by glycogen phosphorylase.
Glycogen synthase and glycogen synthase activity levels are increased (by 100% and 50% compared with WT) in Actn3KO mouse muscle (62). However, when corrected for total glycogen synthase levels, the percentage activity of glycogen synthase is not increased. Glycogen synthase activity is regulated by a number of factors including phosphorylation, activation by glucose 6-phosphate, insulin, and exercise. Existing evidence suggests that, when glycogen content is high, strong feedback decreases glycogen synthase activity, making glycogen synthase the rate-limiting step in glycogenesis (38). Elevation of total glycogen synthase and active glycogen synthase in the presence of elevated glycogen in the Actn3 KO mouse suggests there may be some additional feedback mechanism in the presence of α-actinin-3 deficiency that combats the expected reduction in glycogen synthase activity in this state.
α-Actinin-3 Deficiency Results in Reduced Glycogen Phosphorylase Activity in Muscle
The key enzyme in glycogenolysis, glycogen phosphorylase (GPh), is significantly reduced in Actn3 KO mouse muscle (62). Enzyme quantitation shows activity in the Actn3 KO mouse muscle is 26% compared with 53% in WT mice. An interaction between glycogen phosphorylase and sarcomeric α-actinins has previously been reported (18). By confocal microscopy, we have also shown that α-actinin-3 and glycogen phosphorylase colocalize at the Z-line.
A reduced capacity to break down glycogen for energy would likely be disadvantageous to sprint athletes, who rely on endogenous fuels such as muscle glycogen to rapidly produce energy for contraction. Reduced availability of glucose may, in turn, result in a compensatory shift toward aerobic metabolism, as observed in Actn3 KO mice. Such changes could be advantageous to endurance athletes, allowing them to preferentially use other fuels such as fatty acids for energy generation.
At the electron microscopic (EM) level, Actn3 KO muscle type 2B fibers contain concentric ring-like structures surrounded by and filled by glycogen particles (FIGURE 3C). These structures also stain with antibodies to glycogen phosphorylase and Z-line proteins desmin and myotilin (62) (FIGURE 4).
Glycogen is typically stored near the contractile apparatus of muscle. However, when glycogen stores located at the contractile apparatus are filled up, further glycogen synthesis can occur in other regions of the cell (54). The glycogen accumulations that we see in Actn3 KO mouse muscle may reflect increased glycogen storage and loosening of the association between glycogen and the myofibril. Alternately, α-actinin-3 deficiency may destabilize complexes usually reliant on α-actinin-3 homodimers or heterodimers for structural integrity, leading to displacement of glycogen from its usual location within the muscle fiber (43).
Utilizing global proteomic analysis, we found differential expression of phosphorylated forms of GPh in Actn3 KO muscle compared with WT (62). Since phosphorylation is one of the methods by which GPh activity is regulated, we hypothesise that α-actinin-3 plays a role in regulation of GPh activity by altering its posttranslational phosphorylation and that α-actinin-3 deficiency results in decreased activity of GPh due to altered phosphorylation. The reduction in GPh activity may explain the observed increase in muscle glycogen content and decrease the capacity of muscle to use glycogen as a fuel. This, in turn, could explain the switch in preferred fuel source, from anaerobic metabolism toward more oxidative metabolism as seen in Actn3 KO mice.
α-Actinin-3 Deficiency: A Pretrained State for Improved Endurance and Poorer Sprint Performance?
The improved endurance performance in Actn3 KO mice and in ACTN3 577XX humans, and the shift in muscle metabolism toward a slow oxidative phenotype with increased glycogen content in Actn3 KO mice are all consistent with α-actinin-3-deficient muscle being “pretrained” for endurance performance. It has long been argued that there is an evolutionary trade-off between sprint and endurance performance, as well as a functional trade-off between the effects of endurance and resistance training (34). Sprint and resistance training utilize exercise of short duration and high intensity, resulting in muscle hypertrophy, with increased fiber cross-sectional area, protein content, and an increased ability to generate force (1, 14, 21, 73). Endurance training (in which the length of exercise is increased and intensity is reduced) induces a shift in skeletal muscle metabolism toward a more oxidative form of metabolism.
Oxidative metabolism produces a longer lasting and more stable supply of ATP, making oxidative fibers more fatigue resistant. Endurance training results in reduced fast-fiber cross-sectional area, increased mitochondrial mass, increased oxidative enzymes, and reduced glycolytic enzymes (37, 60, 71, 74). Training for both strength and endurance appears to limit the amount of strength gains an individual can make, suggesting that endurance training may somehow limit skeletal muscle growth (36).
It is possible, therefore, that improved endurance capacity in the presence of α-actinin-3 deficiency may result in a limitation in explosive/power abilities. Unfortunately, there are not adequate or reliable methods by which to test sprint capacity in mice. However, the presence of reduced grip strength in Actn3 KO mice compared with WT does suggest a reduction in explosive power.
Exercise training improves utilization of fat as an energy source and reduces the rate at which glycogen is utilized, thereby delaying glycogen depletion. Similar to our Actn3 KO mouse, exercise training results in higher glycogen stores. Also similar to our Actn3 KO mice, endurance training in humans has been shown to result in increased hexokinase activity and reduced lactate dehydrogenase in muscle (6, 41, 52, 69). A reduction in LDH can result in poorer sprint performance since LDH is needed to convert pyruvate, the final product of glycolysis, to lactate when oxygen is absent or in short supply.
How Does α-Actinin-3 Alter Skeletal Muscle Metabolism?
Historically, the sarcomeric α-actinins have been considered primarily structural proteins, but we have mounting evidence that the principle role of α-actinin-3 is an effect on muscle metabolism and that it has evolved specialized expression in fast muscle fibers because of an important role in the regulation of energy metabolism.
We have shown that α-actinin-3 colocalizes with and increases glycogen phosphorylase activity, but the precise molecular mechanisms involved are yet to be determined. There is strong evidence to suggest that glycogen levels play a role in regulating how fuel is utilized in muscle. Increased muscle glycogen has been shown to increase carbohydrate oxidation during exercise (4, 12, 22, 79). When glycogen is depleted, skeletal muscle may also oxidize free fatty acids to produce ATP and preserve muscle glycogen (61). If muscle glycogen is low before exercise, there is a shift toward decreased carbohydrate oxidation and increased lipid oxidation.
Patients with McArdle's disease lack functional glycogen phosphorylase in muscle and cannot break down glycogen stores. These patients suffer from exercise intolerance and a shift toward lipid utilization for fuel (44). Interestingly, the ACTN3 577XX genotype is associated with improved muscle performance in these patients (45). The mechanism by which α-actinin-3 deficiency improves exercise tolerance in these patients is unknown. Given that most patients with McArdle's disease have no functional muscle glycogen phosphorylase and are therefore unable to utilize glycogen stores, it is unlikely that increased muscle glycogen would improve exercise capacity in these patients. It is possible that the increased fatty acid oxidation capacity seen in Actn3 KO mice could improve fuel utilization in the absence of glycogenolysis, however, this functional link is yet to be tested.
Interestingly, sprint training also increases the ability for rapid glycogen breakdown (glycogenolysis) during shirt bursts of maximal or submaximal activity. It is interesting to speculate whether reduced glycogen phosphorylase activity associated with α-actinin-3 deficiency might reduce the ability to utilize glycogen during sprint activity.
We are in the process of trying to unravel the pathway of events that lead to the metabolic phenotype in Actn3 KO mice. We have examined the time course of appearance of the structural and metabolic phenotypes in Actn3 KO muscle. The reduction of glycogen phosphorylase activity, higher muscle glycogen content, and increased glycolytic and mitochondrial enzymes occur concurrently at ∼4 wk postnatally. These metabolic changes are preceded by upregulation of α-actinin-2 and interacting proteins at the Z-line, suggesting that structural alterations may lie upstream of the metabolic changes. Since α-actinin-2 and -3 and glycogen phosphorylase are colocated at the Z-line, loss of α-actinin-3 may alter the three-dimensional conformation of the Z-line, which in turn could alter the availability of glycogen phosphorylase for phosphorylation and activation. Alternately, the structural and metabolic effects of α-actinin-3 deficiency may be due to independent and unrelated actions of the α-actinin-3 protein.
A review of the known interaction partners of the sarcomeric α-actinins provide tantalizing hints at alternate possible mechanisms underlying the effects of α-actinin-3 on metabolism. In addition to their structural cross-linking functions at the Z-line, the α-sarcomeric α-actinins interact with a number of signaling molecules. α-Actinin-2 and -3 interact with the calsarcin family of proteins, which, through their interaction with calcineurin, are involved in muscle fiber-type determination and regulation of expression of fiber type-specific genes (17, 27, 30, 31, 72). α-Actinin-2 has been shown to interact with membrane-bound signaling proteins such as the NMDA glutamate receptor, Kv1.4 and Kv1.5 potassium channels, and cardiac L-type calcium channels (23, 64, 80, 81).
The α-actinins also bind to the soluble signaling factors phosphoinositol 3-kinase (PI3K) and phosphoinositol-4,5-bisphosphate (PIP2), and G-protein-coupled receptor kinase (29, 32, 68). PIP2 acts as a substrate for enzymes as well as promoting the recruitment of proteins to the plasma membrane and subsequent activation of signaling cascades. In the presence of α-actinin-3 deficiency, any alteration of total α-actinin levels or differential binding between α-actinin-2 and α-actinin-3 could affect regulation of one or many of these important signaling pathways.
Over one billion people worldwide are deficient in α-actinin-3, and there is increasing evidence to suggest that ACTN3 genotype is an important genetic variant that influences the metabolic function of human muscle. α-Actinin-3 deficiency results in a fundamental shift in metabolism away from the anaerobic pathway toward the oxidative pathways of muscle metabolism, which provides an explanation for the association between α-actinin-3 deficiency, poorer sprint and power performance, and enhanced endurance performance. The increase in metabolic efficiency of α-actinin-3-deficient muscle could also provide an explanation for the adaptive benefit of the 577X allele during recent human evolution. The next challenge will be to dissect the molecular mechanisms underlying this metabolic phenotype and explore whether ACTN3 genotype influences glucose homeostasis and adaptive responses to diet in the modern world.
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