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Gain of function AMP ‐activated protein kinase γ 3 mutation ( AMPK γ 3 R200Q ) in pig muscle increases glycogen storage regardless of AMPK activation
Author(s) -
Scheffler Tracy L.,
Park Sungkwon,
Roach Peter J.,
Gerrard David E.
Publication year - 2016
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.12802
Subject(s) - ampk , glycogen , amp activated protein kinase , protein kinase a , medicine , endocrinology , glycogen synthase , glycogen debranching enzyme , chemistry , hexokinase , phosphorylation , biology , glycolysis , biochemistry , metabolism
Chronic activation of AMP ‐activated protein kinase ( AMPK ) increases glycogen content in skeletal muscle. Previously, we demonstrated that a mutation in the ryanodine receptor (RyR1 R615C ) blunts AMPK phosphorylation in longissimus muscle of pigs with a gain of function mutation in the AMPK γ 3 subunit ( AMPK γ 3 R200Q ); this may decrease the glycogen storage capacity of AMPK γ 3 R200Q  + RyR1 R615C muscle. Therefore, our aim in this study was to utilize our pig model to understand how AMPK γ 3 R200Q and AMPK activation contribute to glycogen storage and metabolism in muscle. We selected and bred pigs in order to generate offspring with naturally occurring AMPK γ 3 R200Q , RyR1 R615C , and AMPK γ 3 R200Q  + RyR1 R615C mutations, and also retained wild‐type littermates (control). We assessed glycogen content and parameters of glycogen metabolism in longissimus muscle. Regardless of RyR1 R615C , AMPK γ 3 R200Q increased the glycogen content by approximately 70%. Activity of glycogen synthase ( GS ) without the allosteric activator glucose 6‐phosphate (G6P) was decreased in AMPK γ 3 R200Q relative to all other genotypes, whereas both AMPK γ 3 R200Q and AMPK γ 3 R200Q  + RyR1 R615C 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, AMPK γ 3 R200Q enhanced UDP ‐glucose pyrophosphorylase 2 ( UGP 2) expression approximately threefold. Although UGP 2 is not generally considered a rate‐limiting enzyme for glycogen synthesis, our model suggests that UGP 2 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 AMPK γ 3 R200Q mutation than activity.

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