ORM Promotes Skeletal Muscle Glycogen Accumulation via CCR5-Activated AMPK Pathway in Mice.
We found previously that acute phase protein orosomucoid reacts to fatigue and activates C-C chemokine receptor type 5 to increase muscle glycogen storage and enhance muscle endurance (Lei et al., 2016). To explore the underlying molecular mechanisms, we investigated the role of AMP-activated protein kinase, a critical fuel sensor in skeletal muscle, in C-C chemokine receptor type 5-mediated orosomucoid action. It was found orosomucoid increased skeletal muscle AMP-activated protein kinase activation in a time- and dose- dependent manner, which was largely prevented by pharmacological blocking or knockout of C-C chemokine receptor type 5. Administration of orosomucoid also significantly increased the de-phosphorylation and activity of muscle glycogen synthase, the rate-limiting enzyme for glycogen synthesis. The effect was largely absent in mice deficient in C-C chemokine receptor type 5(-/-) or AMP-activated protein kinase α2(-/-), the predominant isoform in skeletal muscle. Moreover, deletion of AMP-activated protein kinase α2 abolished the effect of orosomucoid on fatigue and muscle glycogen. These findings indicate that orosomucoid may promote glycogen storage and enhance muscle function through C-C chemokine receptor type 5-mdiated activation of AMP-activated protein kinase, which in turn activates glycogen synthase and increases muscle glycogen.
Department of Pharmacology, School of Pharmacy, Second Military Medical University Shanghai, China.
Zhen
Z
Qin
Department of Pharmacology, School of Pharmacy, Second Military Medical University Shanghai, China.
Jing-Jing
JJ
Wan
Department of Pharmacology, School of Pharmacy, Second Military Medical University Shanghai, China.
Yang
Y
Sun
Department of Pharmacology, School of Pharmacy, Second Military Medical University Shanghai, China.
Peng-Yuan
PY
Wang
Department of Pharmacology, School of Pharmacy, Second Military Medical University Shanghai, China.
Ding-Feng
DF
Su
Department of Pharmacology, School of Pharmacy, Second Military Medical University Shanghai, China.
Hong
H
Lei
Department of Pharmacology, School of Pharmacy, Second Military Medical University Shanghai, China.
Xia
X
Liu
AMPK; CCR5; glycogen; orosomucoid; skeletal muscle
J Mol Med (Berl). 2014 Jun;92(6):641-50
24509886
J Biol Chem. 2010 Jul 16;285(29):22174-85
20442402
J Biol Chem. 2012 Aug 24;287(35):29406-16
22782897
J Mol Med (Berl). 2015 Sep;93(9):955-62
26199112
Mol Endocrinol. 2014 Jan;28(1):116-26
24264575
Physiology (Bethesda). 2006 Feb;21:48-60
16443822
Am J Physiol Cell Physiol. 2007 Oct;293(4):C1395-403
17687000
Cell Commun Signal. 2013 Sep 18;11:68
24047437
J Clin Invest. 2007 May;117(5):1432-9
17431505
J Appl Physiol (1985). 1999 Nov;87(5):1990-5
10562646
PLoS One. 2015 Jun 17;10(6):e0130769
26083642
J Clin Invest. 2003 Jan;111(1):91-8
12511592
Diabetes. 2016 Jun;65(6):1630-41
27207522
Muscle Nerve. 1989 Nov;12(11):938-42
2608089
Cell Metab. 2005 Jul;2(1):21-33
16054096
Biochem J. 1998 Nov 15;336 ( Pt 1):19-31
9806880
J Basic Clin Physiol Pharmacol. 1998;9(2-4):139-51
10212831
FASEB J. 2007 Dec;21(14):4059-69
17675532
Am J Physiol Endocrinol Metab. 2007 Mar;292(3):E802-11
17106064
Diabetes Res Clin Pract. 2007 Sep;77 Suppl 1:S92-8
17452058
Nature. 2002 Jan 17;415(6869):339-43
11797013
Mol Cell. 2001 May;7(5):1085-94
11389854
J Appl Physiol (1985). 2000 Mar;88(3):1072-5
10710405
Cell Metab. 2007 Apr;5(4):237-52
17403369
Diabetes. 2011 Mar;60(3):766-74
21282366
EMBO J. 2005 May 18;24(10):1810-20
15889149
Front Pharmacol. 2014 Jun 11;5:140
24966836
J Mol Med (Berl). 2014 Jun;92(6):603-14
24626935
Sci Rep. 2016 Jan 07;6:18839
26740279
FASEB J. 2014 Jul;28(7):3211-24
24652947
J Physiol Biochem. 2015 Jun;71(2):329-40
25711902
Front Biosci (Landmark Ed). 2009 Jan 01;14:19-44
19273052
PLoS One. 2013 Apr 19;8(4):e62190
23620811
Curr Opin Clin Nutr Metab Care. 2008 May;11(3):227-32
18403917
Front Pharmacol. 2015 Mar 09;6:40
25805993
Am J Physiol Heart Circ Physiol. 2000 May;278(5):H1725-31
10775154
FEBS Lett. 2003 Jul 3;546(1):127-32
12829248
Med Sci (Paris). 2003 May;19(5):541-2
12836387
J Mol Med (Berl). 2015 Apr;93(4):413-25
25394677
Cell Metab. 2005 Jan;1(1):15-25
16054041
J Biol Chem. 1996 Nov 1;271(44):27879-87
8910387
Biochem Soc Trans. 2003 Feb;31(Pt 1):236-41
12546693