Overload-induced skeletal muscle extracellular matrix remodelling and myofibre growth in mice lacking IL-6.
OBJECTIVE
Overloading healthy skeletal muscle produces myofibre hypertrophy and extracellular matrix remodelling, and these processes are thought to be interdependent for producing muscle growth. Inflammatory cytokine interleukin-6 (IL-6) gene expression is induced in overloaded skeletal muscle, and the loss of this IL-6 induction can attenuate the hypertrophic response to overload (OV). Although the OV induction of IL-6 in skeletal muscle may be an important regulator of inflammatory processes and satellite cell proliferation, less is known about its role in the regulation of extracellular matrix remodelling. The purpose of the current study was to examine if OV-induced extracellular matrix remodelling, muscle growth, and associated gene expression were altered in mice that lack IL-6, when compared with wild-type mice.


METHODS
Male C57/BL6 (WT) and C57/BL6 x IL-6(-/-) (IL-6(-/-)) mice (10 weeks of age) were assigned to either a sham control or synergist ablation OV treatments for 3, 21 or 56 days.


RESULTS
Plantaris muscle mass increased 59% in WT and 116% in IL-6(-/-) mice after 21 day OV. Myofibre CSA was also increased by 21 day OV in both WT and IL-6(-/-) mice. OV induced a twofold greater increase in the volume of non-contractile tissue in IL-6(-/-) muscle compared to WT. OV also induced a significantly greater accumulation of hydroxyproline and procollagen-1 mRNA in IL-6(-/-) muscle, when compared with WT muscle after 21 day OV. Transforming growth factor-beta and insulin-like growth factor-1 mRNA expression were also induced to a greater extent in IL-6(-/-) muscle when compared with WT muscle after 21 day OV. There was no effect of IL-6 loss on the induction of myogenin, and cyclin D1 mRNA expression after 3 day OV. However, MyoD mRNA expression in 3 day OV IL-6(-/-) muscle was attenuated when compared with WT OV mice.


CONCLUSIONS
IL-6 appears to be necessary for the normal regulation of extracellular matrix remodelling during OV-induced growth.
White
J P
JP
Exercise Science Department, University of South Carolina, Columbia, 29208, USA.
Reecy
J M
JM
Washington
T A
TA
Sato
S
S
Le
M E
ME
Davis
J M
JM
Wilson
L B
LB
Carson
J A
JA
D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism*; D006984:Hypertrophy / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000502:physiology*; D018482:Muscle, Skeletal / Q000033:anatomy & histology / Q000254:growth & development; D009929:Organ Size; D011347:Procollagen / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D016474:Weight-Bearing / Q000502:physiology*
D015850:Interleukin-6; D011347:Procollagen; D016212:Transforming Growth Factor beta; D007334:Insulin-Like Growth Factor I
Ann Neurol. 2002 Dec;52(6):832-6
12447939
FASEB J. 2002 Sep;16(11):1335-47
12205025
Muscle Nerve. 2003 Sep;28(3):365-72
12929198
J Biol Chem. 2002 Mar 1;277(9):7076-85
11751884
Am J Physiol Regul Integr Comp Physiol. 2005 Feb;288(2):R345-53
15637171
Am J Physiol Regul Integr Comp Physiol. 2003 Nov;285(5):R1076-85
14557238
Biochem Biophys Res Commun. 1995 Nov 2;216(1):49-53
7488123
J Clin Invest. 1998 Jan 15;101(2):311-20
9435302
J Histochem Cytochem. 2000 Sep;48(9):1203-13
10950877
Mol Ther. 2007 Sep;15(9):1616-22
17609657
Diabetes. 2003 Nov;52(11):2784-9
14578297
J Appl Physiol (1985). 2006 Jun;100(6):2012-23
16497837
Circulation. 2005 Mar 1;111(8):996-1005
15710765
Am J Physiol Regul Integr Comp Physiol. 2005 Jun;288(6):R1543-52
15886356
Eur J Cell Biol. 1995 Nov;68(3):330-5
8603686
Am J Physiol. 1982 May;242(5):C333-8
6177250
J Appl Physiol (1985). 2004 Oct;97(4):1424-30
15358753
J Cell Physiol. 2005 Aug;204(2):428-36
15717324
Nature. 1994 Mar 24;368(6469):339-42
8127368
J Appl Physiol (1985). 1999 Nov;87(5):1705-12
10562612
J Biol Chem. 1987 May 15;262(14):6443-6
3471760
Am J Physiol Cell Physiol. 2002 Jul;283(1):C204-11
12055089
Biochem Biophys Res Commun. 1995 Feb 6;207(1):168-74
7857261
J Appl Physiol (1985). 2005 Mar;98(3):911-7
15542570
Am J Physiol Endocrinol Metab. 2001 May;280(5):E745-51
11287357
Physiol Rev. 2004 Jan;84(1):209-38
14715915
Cytokine. 2006 May;34(3-4):125-30
16781162
J Appl Physiol (1985). 2001 Aug;91(2):693-702
11457783
Am J Pathol. 2004 Mar;164(3):1007-19
14982854
Am J Physiol. 1985 Sep;249(3 Pt 1):C352-5
4037076
J Clin Invest. 1996 Jan 1;97(1):244-9
8550842
Exp Gerontol. 2006 Nov;41(11):1136-48
17064867
Biochem Biophys Res Commun. 2003 Oct 17;310(2):550-4
14521945
J Appl Physiol (1985). 2003 Mar;94(3):1153-61
12571141
Exerc Sport Sci Rev. 2003 Jul;31(3):111-6
12882475
Clin Chim Acta. 1967 Nov;18(2):267-73
4864804
J Invest Dermatol. 2007 Mar;127(3):526-37
17299435
Am J Physiol Cell Physiol. 2003 Aug;285(2):C391-8
12711594
Am J Physiol Cell Physiol. 2005 Nov;289(5):C1179-87
16079187
J Appl Physiol (1985). 2009 Feb;106(2):443-53
19057004
J Appl Physiol (1985). 2005 Jun;98(6):2219-25
15894538
Biochem J. 2003 Aug 15;374(Pt 1):1-20
12773095
Nat Med. 2002 Jan;8(1):75-9
11786910
Regul Pept. 2005 Jan 15;124(1-3):65-72
15544842
Mol Biol Cell. 2004 Apr;15(4):2013-26
14767066
Physiol Rev. 2004 Apr;84(2):649-98
15044685
FASEB J. 2002 Feb;16(2):207-9
11744623
Cell Metab. 2008 Jan;7(1):33-44
18177723
Pflugers Arch. 2009 Mar;457(5):989-1001
18712412
Proc Nutr Soc. 2004 May;63(2):351-6
15294054
Am J Physiol Regul Integr Comp Physiol. 2008 Feb;294(2):R393-401
18056981