Alpha-actinin-3 deficiency results in reduced glycogen phosphorylase activity and altered calcium handling in skeletal muscle.
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 alpha-actinin-3. ACTN3 genotype is associated with human athletic performance and alpha-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. alpha-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 alpha-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 alpha-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 alpha-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 alpha-actinin-3 is a fundamental mechanistic link in the association between ACTN3 genotype and human performance.
Quinlan
Kate G R
KG
Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, NSW, Australia.
Seto
Jane T
JT
Turner
Nigel
N
Vandebrouck
Aurelie
A
Floetenmeyer
Matthias
M
Macarthur
Daniel G
DG
Raftery
Joanna M
JM
Lek
Monkol
M
Yang
Nan
N
Parton
Robert G
RG
Cooney
Gregory J
GJ
North
Kathryn N
KN
D000185:Actinin / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D054874:Athletic Performance; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006003:Glycogen / Q000378:metabolism; D024981:Glycogen Phosphorylase / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies / Q000201:enzymology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology*; D032446:Myoblasts / Q000378:metabolism; D011499:Protein Processing, Post-Translational
C118456:ACTN3 protein, human; D000185:Actinin; D006003:Glycogen; D024981:Glycogen Phosphorylase; D002118:Calcium