title: Insulin-like 6 is induced by muscle injury and functions as a regenerative factor.
abstract: The insulin-like family of factors are involved in the regulation of a variety of physiological processes, but the function of the family member termed insulin-like 6 (Insl6) in skeletal muscle has not been reported. We show that Insl6 is a myokine that is up-regulated in skeletal muscle downstream of Akt signaling and in regenerating muscle in response to cardiotoxin (CTX)-induced injury. In the CTX injury model, myofiber regeneration was improved by the intramuscular or systemic delivery of an adenovirus expressing Insl6. Skeletal muscle-specific Insl6 transgenic mice exhibited normal muscle mass under basal conditions but elevated satellite cell activation and enhanced muscle regeneration in response to CTX injury. The Insl6-mediated regenerative response was associated with reductions in muscle cell apoptosis and reduced serum levels of creatine kinase M. Overexpression of Insl6 stimulated proliferation and reduced apoptosis in cultured myogenic cells. Conversely, knockdown of Insl6 reduced proliferation and increased apoptosis. These data indicate that Insl6 is an injury-regulated myokine that functions as a myogenic regenerative factor.
authors.affiliation: Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University Medical Campus, Boston, Massachusetts 02118, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Zeng
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Akasaki
authors.forename: Kaori
authors.initials: K
authors.lastname: Sato
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ouchi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Izumiya
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002460:Cell Line; D004179:Cobra Cardiotoxin Proteins / Q000633:toxicity*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009135:Muscular Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012038:Regeneration; D020133:Reverse Transcriptase Polymerase Chain Reaction; D032496:Satellite Cells, Skeletal Muscle / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
chemical_list: D004179:Cobra Cardiotoxin Proteins; C512664:Insl6 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
references.citation: Brain Res. 2005 Apr 8;1040(1-2):187-90
references.pmid: 15804440
references.citation: Genes Dev. 2006 Jul 1;20(13):1692-708
references.pmid: 16818602
references.citation: J Biol Chem. 1995 May 19;270(20):12109-16
references.pmid: 7744859
references.citation: Nat Genet. 2001 Feb;27(2):195-200
references.pmid: 11175789
references.citation: Curr Opin Clin Nutr Metab Care. 2004 Jul;7(4):451-7
references.pmid: 15192449
references.citation: Curr Opin Pharmacol. 2006 Jun;6(3):301-6
references.pmid: 16563862
references.citation: Ann N Y Acad Sci. 2005 May;1041:520-9
references.pmid: 15956755
references.citation: Muscle Nerve. 2009 Sep;40(3):455-65
references.pmid: 19705426
references.citation: Growth Factors. 1996;13(1-2):37-55
references.pmid: 8962719
references.citation: Biol Reprod. 2000 Jun;62(6):1593-9
references.pmid: 10819760
references.citation: Neuromuscul Disord. 2005 Feb;15(2):117-26
references.pmid: 15694133
references.citation: Mol Cell Biol. 1999 Jul;19(7):5073-82
references.pmid: 10373556
references.citation: Cell Metab. 2008 Feb;7(2):159-72
references.pmid: 18249175
references.citation: Angiogenesis. 2008;11(3):289-99
references.pmid: 18491207
references.citation: Endocrinology. 2009 Sep;150(9):3986-90
references.pmid: 19700610
references.citation: Ann N Y Acad Sci. 2005 May;1041:61-76
references.pmid: 15956688
references.citation: Endocrinology. 2006 Dec;147(12):5611-23
references.pmid: 16935843
references.citation: Am J Physiol Cell Physiol. 2000 Jan;278(1):C174-81
references.pmid: 10644525
references.citation: Endocrinology. 2008 Apr;149(4):1543-50
references.pmid: 18096661
references.citation: J Biol Chem. 2003 Mar 7;278(10):8826-36
references.pmid: 12477723
references.citation: J Cell Physiol. 1989 Feb;138(2):311-5
references.pmid: 2918032
references.citation: Mol Cell Biol. 2002 Jul;22(13):4803-14
references.pmid: 12052887
references.citation: Cardiovasc Res. 2007 Jun 1;74(3):471-9
references.pmid: 17362898
references.citation: J Appl Physiol (1985). 2007 Sep;103(3):1093-8
references.pmid: 17347387
references.citation: PLoS One. 2007 Jun 13;2(6):e527
references.pmid: 17565380
references.citation: J Appl Physiol (1985). 1998 May;84(5):1716-22
references.pmid: 9572822
references.citation: Aging Cell. 2008 Aug;7(4):590-8
references.pmid: 18462272
references.citation: Toxicon. 2008 Mar 15;51(4):624-34
references.pmid: 18221763
references.citation: Stem Cell Rev. 2007 Fall;3(3):226-37
references.pmid: 17917136
references.citation: Exp Gerontol. 2006 May;41(5):497-500
references.pmid: 16580804
references.citation: BMC Evol Biol. 2005 Feb 12;5:14
references.pmid: 15707501
references.citation: Nat Cell Biol. 2001 Nov;3(11):1009-13
references.pmid: 11715022
references.citation: Muscle Nerve. 2003 Sep;28(3):365-72
references.pmid: 12929198
references.citation: Diabetes. 2009 Dec;58(12):2797-801
references.pmid: 19720803
references.citation: Ann N Y Acad Sci. 2005 May;1041:395-7
references.pmid: 15956737
references.citation: Nat Cell Biol. 2001 Nov;3(11):1014-9
references.pmid: 11715023
references.citation: Physiol Rev. 2004 Jan;84(1):209-38
references.pmid: 14715915
references.citation: Am J Pathol. 2004 Mar;164(3):1007-19
references.pmid: 14982854
references.citation: Hum Mol Genet. 2009 Jan 15;18(2):318-27
references.pmid: 18986978
references.citation: Am J Sports Med. 2005 Dec;33(12):1816-24
references.pmid: 16157846
references.citation: Sci Aging Knowledge Environ. 2003 Dec 03;2003(48):pe34
references.pmid: 14657508
references.citation: Nature. 2008 Feb 21;451(7181):1008-12
references.pmid: 18288196
references.citation: J Cell Physiol. 2010 Jul;224(1):7-16
references.pmid: 20232319
references.citation: Ann N Y Acad Sci. 2006 May;1067:349-53
references.pmid: 16804010
references.citation: Cell Transplant. 1998 Nov-Dec;7(6):585-98
references.pmid: 9853587
references.citation: J Bone Joint Surg Br. 2000 Jan;82(1):131-7
references.pmid: 10697329
references.citation: Dev Dyn. 2003 Jun;227(2):256-65
references.pmid: 12761853
references.citation: Brain Behav Immun. 2005 Sep;19(5):371-6
references.pmid: 15935612
references.citation: Physiol Genomics. 2006 Oct 11;27(2):156-70
references.pmid: 16882883
references.citation: Science. 2003 Nov 28;302(5650):1575-7
references.pmid: 14645852
references.citation: Can J Appl Physiol. 1996 Aug;21(4):236-50
references.pmid: 8853466
references.citation: FEBS Lett. 2008 Nov 12;582(27):3805-10
references.pmid: 18948104
references.citation: Histochem Cell Biol. 2004 Nov;122(5):427-34
references.pmid: 15480739
references.citation: Endocrinology. 2009 Sep;150(9):4348-57
references.pmid: 19520787
references.citation: Apoptosis. 2007 Nov;12(11):1965-78
references.pmid: 17786558
references.citation: J Biol Chem. 2008 Nov 21;283(47):32802-11
references.pmid: 18718903
references.citation: Physiol Genomics. 2003 Aug 15;14(3):261-71
references.pmid: 12799472
references.citation: Mol Cell Biol. 1988 Jul;8(7):2896-909
references.pmid: 3405222
references.citation: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5416-21
references.pmid: 10792059