α-Actinin-3 deficiency results in reduced glycogen phosphorylase activity and altered calcium handling in skeletal muscle

Quinlan, Kate G. R., Seto, Jane T., Turner, Nigel, Vandebrouck, Aurelie, Floetenmeyer, Matthias, Macarthur, Daniel G., Raftery, Joanna M., Lek, Monkol, Yang, Nan, Parton, Robert G., Cooney, Gregory J. and North, Kathryn N. (2010) α-Actinin-3 deficiency results in reduced glycogen phosphorylase activity and altered calcium handling in skeletal muscle. Human Molecular Genetics, 19 7: ddq010-1335-ddq010-1346.


Author Quinlan, Kate G. R.
Seto, Jane T.
Turner, Nigel
Vandebrouck, Aurelie
Floetenmeyer, Matthias
Macarthur, Daniel G.
Raftery, Joanna M.
Lek, Monkol
Yang, Nan
Parton, Robert G.
Cooney, Gregory J.
North, Kathryn N.
Title α-Actinin-3 deficiency results in reduced glycogen phosphorylase activity and altered calcium handling in skeletal muscle
Journal name Human Molecular Genetics  (ERA 2012 Listed)    (ERA 2010 Rank A*)   Check publisher's open access policy
Publication date 2010-04
Sub-type Article
DOI 10.1093/hmg/ddq010
Volume number 19
Issue number 7
ISSN 0964-6906
1460-2083
Start page ddq010-1335
End page ddq010-1346
Total pages 12
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Collection year 2011
Language eng
Subject 1104 Complementary and Alternative Medicine
0604 Genetics
Formatted abstract 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 α-actinin-3. ACTN3 genotype is associated with human athletic performance and α-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. α-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 α-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 α-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 α-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 α-actinin-3 is a fundamental mechanistic link in the association between ACTN3 genotype and human performance.
Copyright © 2011 Oxford University Press


Keyword Chicken Pectoralis-Muscle
Actn3 R577x Polymorphism
Alpha-Actinin
Athletic Performance
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article number ddq010

 
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Created: Sun, 04 Apr 2010, 00:05:08 EST