title: Absence of functional leptin receptor isoforms in the POUND (Lepr(db/lb)) mouse is associated with muscle atrophy and altered myoblast proliferation and differentiation.
abstract: OBJECTIVE
  Leptin receptors are abundant in human skeletal muscle, but the role of leptin in muscle growth, development and aging is not well understood. Here we utilized a novel mouse model lacking all functional leptin receptor isoforms (POUND mouse, Lepr(db/lb)) to determine the role of leptin in skeletal muscle.
  
  
  RESULTS
  Skeletal muscle mass and fiber diameters were examined in POUND mice, and primary myoblast cultures were used to determine the effects of altered leptin signaling on myoblast proliferation and differentiation. ELISA assays, integrated pathway analysis of mRNA microarrays, and reverse phase protein analysis were performed to identify signaling pathways impacted by leptin receptor deficiency. Results show that skeletal muscle mass and fiber diameter are reduced 30-40% in POUND mice relative to wild-type controls. Primary myoblast cultures demonstrate decreased proliferation and decreased expression of both MyoD and myogenin in POUND mice compared to normal mice. Leptin treatment increased proliferation in primary myoblasts from muscles of both adult (12 months) and aged (24 months) wild-type mice, and leptin increased expression of MyoD and myogenin in aged primary myoblasts. ELISA assays and protein arrays revealed altered expression of molecules associated with the IGF-1/Akt and MAPK/MEK signaling pathways in muscle from the hindlimbs of mice lacking functional leptin receptors.
  
  
  CONCLUSIONS
  These data support the hypothesis that the adipokine leptin is a key factor important for the regulation of skeletal muscle mass, and that leptin can act directly on its receptors in peripheral tissues to regulate cell proliferation and differentiation.
authors: Georgia Regents University, Augusta, Georgia, United States of America.
authors: Phonepasong
authors: P
authors: Arounleut
authors: Matthew
authors: M
authors: Bowser
authors: Sunil
authors: S
authors: Upadhyay
authors: Xing-Ming
authors: XM
authors: Shi
authors: Sadanand
authors: S
authors: Fulzele
authors: Maribeth H
authors: MH
authors: Johnson
authors: Alexis M
authors: AM
authors: Stranahan
authors: William D
authors: WD
authors: Hill
authors: Carlos M
authors: CM
authors: Isales
authors: Mark W
authors: MW
authors: Hamrick
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D015536:Down-Regulation; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology; D009133:Muscular Atrophy / Q000378:metabolism*; D017570:MyoD Protein / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism; D018008:Myogenin / Q000378:metabolism; D055435:Myostatin / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D019899:Paracrine Communication; D020033:Protein Isoforms / Q000172:deficiency; D054411:Receptors, Leptin / Q000172:deficiency*
chemical_list: D017570:MyoD Protein; D018008:Myogenin; D055435:Myostatin; D020033:Protein Isoforms; D054411:Receptors, Leptin; D007334:Insulin-Like Growth Factor I
references: Nature. 1998 Jun 18;393(6686):684-8
references: 9641678
references: Int J Obes Relat Metab Disord. 2000 Aug;24(8):1040-50
references: 10951544
references: Curr Top Microbiol Immunol. 2010;346:267-78
references: 20593312
references: Exp Gerontol. 2013 Feb;48(2):290-7
references: 23178301
references: Endocrinology. 2011 Jan;152(1):172-80
references: 21147879
references: Biosci Biotechnol Biochem. 2008 Jan;72(1):13-21
references: 18175932
references: J Anim Physiol Anim Nutr (Berl). 2013 Oct;97(5):887-95
references: 22853698
references: ScientificWorldJournal. 2011 Jul 28;11:1525-35
references: 21805021
references: Mol Cell Endocrinol. 2003 Mar 28;201(1-2):109-21
references: 12706299
references: J Clin Endocrinol Metab. 1998 May;83(5):1407-13
references: 9589630
references: J Cell Biochem. 2005 Sep 1;96(1):89-96
references: 16052473
references: Biochem Biophys Res Commun. 2010 Sep 24;400(3):379-83
references: 20800581
references: J Biol Chem. 1997 Mar 7;272(10):6653-62
references: 9045696
references: Curr Opin Clin Nutr Metab Care. 2008 May;11(3):303-8
references: 18403928
references: J Clin Endocrinol Metab. 2008 Jul;93(7):2819-27
references: 18445667
references: J Bone Miner Res. 2008 Jun;23(6):870-8
references: 18435579
references: Am J Physiol Endocrinol Metab. 2008 May;294(5):E918-27
references: 18334608
references: Eur J Endocrinol. 2000 Jan;142(1):25-9
references: 10633217
references: Cell. 2001 Feb 23;104(4):531-43
references: 11239410
references: Bone. 2004 Mar;34(3):376-83
references: 15003785
references: JAMA. 1980 May 2;243(17):1720-2
references: 6767862
references: Eur J Appl Physiol. 2010 Mar;108(4):749-58
references: 20187280
references: Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):10092-7
references: 16782821
references: N Engl J Med. 2004 Sep 2;351(10):987-97
references: 15342807
references: Br Med Bull. 2010;95:139-59
references: 20200012
references: J Bone Miner Res. 2005 Jun;20(6):994-1001
references: 15883640
references: Endocrinology. 2009 Jan;150(1):286-94
references: 18801898
references: J Appl Physiol (1985). 2007 May;102(5):1786-92
references: 17234799
references: Bone. 2006 Oct;39(4):845-53
references: 16750436
references: Cell Biol Int. 2005 Jul;29(7):542-50
references: 15979910
references: Physiol Genomics. 2007 Nov 14;31(3):510-20
references: 17804603
references: J Bone Miner Res. 2004 Oct;19(10):1607-11
references: 15355554
references: Int J Obes Relat Metab Disord. 2002 Nov;26(11):1407-33
references: 12439643
references: J Cell Biol. 1994 Jun;125(6):1275-87
references: 8207057
references: Methods Cell Biol. 1997;52:261-72
references: 9379953
references: Cytokine. 2013 Feb;61(2):445-54
references: 23201486
references: J Bone Miner Res. 2011 Aug;26(8):1710-20
references: 21520275
references: PLoS One. 2009 Sep 04;4(9):e6808
references: 19730740
references: J Bone Miner Res. 2013 Jan;28(1):22-34
references: 22887758
references: Diabetes. 2011 Apr;60(4):1258-69
references: 21346177
references: Science. 2003 Dec 5;302(5651):1710-1
references: 14657487
references: Calcif Tissue Int. 2002 Apr;70(4):305-11
references: 12004335
references: Am J Physiol Cell Physiol. 2009 Jun;296(6):C1258-70
references: 19357233