A gene for speed: contractile properties of isolated whole EDL muscle from an α-actinin-3 knockout mouse

Chan, Stephen; Seto, Jane T.; MacArthur, Daniel G.; Yang, Nan; North, Klaus; Head, Stewart I.

doi:10.1152/ajpcell.00179.2008

Cited by 84 publications

(88 citation statements)

References 17 publications

(29 reference statements)

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“…Interestingly, the twitch/tetanus ratio in EDL muscles from IL-15Rα-KO mice was 15% lower than in EDL muscles from control mice. The lower value for the twitch/tetanus ratio observed in this study is consistent with a previous report noting lower twitch/tetanus ratio values in muscles composed of slower motor units (43), and similar findings have been previously reported in the Actn3-KO mouse (40). In addition, the altered rates of force development and relaxation suggest alterations in the regulation of intracellular calcium levels following maximal contractions, as are noted to occur in slow skeletal muscles (44).…”

Section: Discussionsupporting

confidence: 93%

“…This study provides physiological and molecular data demonstrating that loss of IL-15Rα in vivo results in remodeling of fast muscles to a slower, more oxidative phenotype, akin to the roles proposed for PGC-1α and ACTN3 (40,41). These observations were specific to the loss of IL-15Rα, as knockout of IL-15 and transgenic overexpression of IL-15 did not result in altered exercise and muscle phenotypes.…”

Section: Discussionsupporting

confidence: 52%

“…Also, compared with an EDL muscle from a control mouse, the fatigue curve was shifted entirely to the right during the first 70 seconds of the repeated stimulation protocol, after which the fatigue curves of EDL muscles from B6129 control and IL-15Rα-KO mice were not different. Previous studies have reported an increase in fatigue resistance in EDL muscles following genetic manipulation of Actn3 (40) and Pgc-1α (41), although differing fatigue protocols preclude direct comparison with the current data in the IL-15Rα-KO mouse.…”

Section: Discussionmentioning

confidence: 68%

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Loss of IL-15 receptor α alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles

Pistilli¹,

Bogdanovich²,

Garton³

et al. 2011

J. Clin. Invest.

128

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IL-15 receptor α (IL-15Rα) is a component of the heterotrimeric plasma membrane receptor for the pleiotropic cytokine IL-15. However, IL-15Rα is not merely an IL-15 receptor subunit, as mice lacking either IL-15 or IL-15Rα have unique phenotypes. IL-15 and IL-15Rα have been implicated in muscle phenotypes, but a role in muscle physiology has not been defined. Here, we have shown that loss of IL-15Rα induces a functional oxidative shift in fast muscles, substantially increasing fatigue resistance and exercise capacity. IL-15Rα-knockout (IL-15Rα-KO) mice ran greater distances and had greater ambulatory activity than controls. Fast muscles displayed fatigue resistance and a slower contractile phenotype. The molecular signature of these muscles included altered markers of mitochondrial biogenesis and calcium homeostasis. Morphologically, fast muscles had a greater number of muscle fibers, smaller fiber areas, and a greater ratio of nuclei to fiber area. The alterations of physiological properties and increased resistance to fatigue in fast muscles are consistent with a shift toward a slower, more oxidative phenotype. Consistent with a conserved functional role in humans, a genetic association was found between a SNP in the IL15RA gene and endurance in athletes stratified by sport. Therefore, we propose that IL-15Rα has a role in defining the phenotype of fast skeletal muscles in vivo.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 68%

See 1 more Smart Citation

Loss of IL-15 receptor α alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles

Pistilli¹,

Bogdanovich²,

Garton³

et al. 2011

J. Clin. Invest.

128

View full text Add to dashboard Cite

show abstract

“…For instance, we have recently shown that the common 577X stop-codon mutation within the gene encoding sarcomeric alpha-actinin 3 (ACTN3) is associated with lower cardiovascular fitness (peak VO 2 ), increased body fat and an atherogenic metabolite profile relative to carriers of the R577 ancestral allele (Deschamps et al 2015). These findings support a large body of published research linking the ACTN3 "sports gene" to exercise capacity in both elite and amateur athletes (Chan et al 2008;Clarkson et al 2005;Delmonico et al 2007;Eynon et al 2014;MacArthur and North 2004;Mills et al 2001;Norman et al 2014). In this same D r a f t cohort we determined that students enrolled in accredited kinesiology degree programs in Canada and the United States display improved parameters of insulin sensitivity and increased physical activity levels relative to non-kinesiology majors (Many et al 2016).…”

Section: Introductionsupporting

confidence: 77%

Genetic characterization of physical activity behaviours in university students enrolled in kinesiology degree programs

Many

Kendrick

Deschamps

et al. 2017

Appl. Physiol. Nutr. Metab.

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Studies of physical activity behaviours have increasingly shown the importance of heritable factors such as genetic variation. Non-synonymous polymorphisms of alphaactinin 3 (ACTN3) and the β-adrenergic receptors 1 and 3 (ADRB) have been previously associated with exercise capacity and cardiometabolic health. We thus hypothesized that these polymorphisms are also related to physical activity behaviors in young adults. To test this hypothesis we examined relationships between ACTN3 (R577X), ARDB1 (Arg389Gly) and ADRB3 (Trp64Arg), and physical activity behaviors in university students. We stratified for student enrollment in kinesiology degree programs compared to non-majors as we previously found this to be a predictor of physical activity. We did not identify novel associations between physical activity and ACTN3. However, the minor alleles of ADRB1 and ADRB3 were significantly underrepresented in kinesiology students compared to non-majors. Furthermore, carriers of the ADRB1 minor allele reported reduced participation in moderate physical activity and increased afternoon fatigue compared to ancestral allele homozygotes. Together, these findings suggest that the heritability of physical activity behaviours in young adults may be linked to nonsynonymous polymorphisms within β-adrenergic receptors.

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“…In healthy individuals of European decent, ϳ18% are deficient in ACNT3 due to a common nonsense polymorphism in the ACTN3 gene, R577X (76). The early identification of this polymorphism has led to intense investigation as to the role of ACTN3 deficiency in muscle damage, strength/power, and human performance (15,19,56,100,110,119).…”

Section: Longitudinal Force Transmissionmentioning

confidence: 99%

Effects of aging, exercise, and disease on force transfer in skeletal muscle

Hughes

Wallace

Baar

2015

American Journal of Physiology-Endocrinology and Metabolism

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Hughes DC, Wallace MA, Baar K. Effects of aging, exercise, and disease on force transfer in skeletal muscle. Am J Physiol Endocrinol Metab 309: E1-E10, 2015. First published May 12, 2015; doi:10.1152/ajpendo.00095.2015.-The loss of muscle strength and increased injury rate in aging skeletal muscle has previously been attributed to loss of muscle protein (cross-sectional area) and/or decreased neural activation. However, it is becoming clear that force transfer within and between fibers plays a significant role in this process as well. Force transfer involves a secondary matrix of proteins that align and transmit the force produced by the thick and thin filaments along muscle fibers and out to the extracellular matrix. These specialized networks of cytoskeletal proteins aid in passing force through the muscle and also serve to protect individual fibers from injury. This review discusses the cytoskeleton proteins that have been identified as playing a role in muscle force transmission, both longitudinally and laterally, and where possible highlights how disease, aging, and exercise influence the expression and function of these proteins. force transmission; dystrophin-glycoprotein complex; injury; aging ON AVERAGE, HUMANS LOSE AROUND 45% of their muscle mass between their mid-20s and 80s (47,70,71). This loss in muscle mass in the absence of disease is known as sarcopenia (60). The decline in muscle mass is accompanied by, but cannot fully explain, a rapid loss in muscle strength (64). The loss in muscle strength has previously been investigated from the perspectives of loss of muscle protein mass (cross-sectional area) and decreased neural activation. A third possibility, impaired force transfer, has received the least attention in relation to aging, exercise, and disease (66,90,102). However, recent advances in our understanding of this process suggest that force transfer plays an important role in muscle strength and injury prevention, and this fact is the focus of this review. Force TransferOver 60 years ago, Andrew Huxley and his students used electron microscopy to show that during muscle contraction the I-band (containing the thin filament) shortened whereas the A-band (containing the thick filament) remained a constant length (39). Their famous "sliding theory of muscle contraction" provided an image of a muscle shortening end to end as the A-bands drew closer together. Implied in this model is that force is transferred in a longitudinal manner as a result of sarcomere shortening. However, a deeper consideration of this model requires that there be a secondary matrix of proteins that are not visible to the electron microscope, proteins that transmit the force produced by the thick and thin filaments along the muscle fiber to the tendons. These specialized networks of cytoskeletal proteins transmit force through the muscle to the tendon and also serve to protect individual fibers from injury.An important structure in these networks is the "costamere", which connects the sarcolemma with the contractile appar...

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A gene for speed: contractile properties of isolated whole EDL muscle from an α-actinin-3 knockout mouse

Abstract: North KN, Head SI. A gene for speed: contractile properties of isolated whole EDL muscle from an ␣-actinin-3 knockout mouse.

Cited by 84 publications

References 17 publications

Loss of IL-15 receptor α alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles

Loss of IL-15 receptor α alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles

Genetic characterization of physical activity behaviours in university students enrolled in kinesiology degree programs

Effects of aging, exercise, and disease on force transfer in skeletal muscle

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