Gain of function AMP-activated protein kinase γ3 mutation (AMPKγ3R200Q) in pig muscle increases glycogen storage regardless of AMPK activation

Tracy L. Scheffler, Sungkwon Park, Peter J. Roach, David E. Gerrard

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Chronic activation of AMP-activated protein kinase (AMPK) increases glycogen content in skeletal muscle. Previously, we demonstrated that a mutation in the ryanodine receptor (RyR1R615C) blunts AMPK phosphorylation in longissimus muscle of pigs with a gain of function mutation in the AMPKγ3 subunit (AMPKγ3R200Q); this may decrease the glycogen storage capacity of AMPKγ3R200Q + RyR1R615C muscle. Therefore, our aim in this study was to utilize our pig model to understand how AMPKγ3R200Q and AMPK activation contribute to glycogen storage and metabolism in muscle. We selected and bred pigs in order to generate offspring with naturally occurring AMPKγ3R200Q, RyR1R615C, and AMPKγ3R200Q + RyR1R615C mutations, and also retained wild-type littermates (control). We assessed glycogen content and parameters of glycogen metabolism in longissimus muscle. Regardless of RyR1R615C, AMPKγ3R200Q increased the glycogen content by approximately 70%. Activity of glycogen synthase (GS) without the allosteric activator glucose 6-phosphate (G6P) was decreased in AMPKγ3R200Q relative to all other genotypes, whereas both AMPKγ3R200Q and AMPKγ3R200Q + RyR1R615C muscle exhibited increased GS activity with G6P. Increased activity of GS with G6P was not associated with increased abundance of GS or hexokinase 2. However, AMPKγ3R200Q enhanced UDP-glucose pyrophosphorylase 2 (UGP2) expression approximately threefold. Although UGP2 is not generally considered a rate-limiting enzyme for glycogen synthesis, our model suggests that UGP2 plays an important role in increasing flux to glycogen synthase. Moreover, we have shown that the capacity for glycogen storage is more closely related to the AMPKγ3R200Q mutation than activity.

Original languageEnglish (US)
Article numbere12802
JournalPhysiological reports
Volume4
Issue number11
DOIs
StatePublished - Jun 1 2016

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Keywords

  • Calcium
  • UDP-glucose pyrophosphorylase
  • glucose 6 phosphate
  • glycogen synthase
  • skeletal muscle

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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