Altered contractility of skeletal muscle in mice deficient in titin's M-band region.
We investigated the contractile phenotype of skeletal muscle deficient in exons MEx1 and MEx2 (KO) of the titin M-band by using the cre-lox recombination system and a multidisciplinary physiological approach to study skeletal muscle contractile performance. At a maximal tetanic stimulation frequency, intact KO extensor digitorum longus muscle was able to produce wild-type levels of force. However, at submaximal stimulation frequency, force was reduced in KO mice, giving rise to a rightward shift of the force-frequency curve. This rightward shift of the force-frequency curve could not be explained by altered sarcoplasmic reticulum Ca(2+) handling, as indicated by analysis of Ca(2+) transients in intact myofibers and expression of Ca(2)(+)-handling proteins, but can be explained by the reduced myofilament Ca(2+) sensitivity of force generation that we found. Western blotting experiments suggested that the excision of titin exons MEx1 and MEx2 did not result in major changes in expression of titin M-band binding proteins or phosphorylation level of the thin-filament regulatory proteins, but rather in a shift toward expression of slow isoforms of the thick-filament-associated protein, myosin binding protein-C. Extraction of myosin binding protein-C from skinned muscle normalized myofilament Ca(2+) sensitivity of the KO extensor digitorum longus muscle. Thus, our data suggest that the M-band region of titin affects the expression of genes involved in the regulation of skeletal muscle contraction.
Ottenheijm
Coen A C
CA
Department of Physiology, Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85724, USA.
Hidalgo
Carlos
C
Rost
Katharina
K
Gotthardt
Michael
M
Granzier
Henk
H
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis; D064211:Connectin; D005091:Exons; D051379:Mice; D008954:Models, Biological; D009119:Muscle Contraction; D009124:Muscle Proteins / Q000172:deficiency*; D018482:Muscle, Skeletal / Q000502:physiology*; D011494:Protein Kinases / Q000172:deficiency*; D011995:Recombination, Genetic; D017384:Sequence Deletion; D000099163:Myosin Binding Protein C
D002118:Calcium; D002352:Carrier Proteins; D064211:Connectin; D009124:Muscle Proteins; D011494:Protein Kinases; D000099163:Myosin Binding Protein C
Biophys J. 1995 Mar;68(3):1027-44
7756523
J Muscle Res Cell Motil. 2005;26(6-8):381-8
16470336
Circ Res. 2008 Aug 1;103(3):244-51
18599866
J Struct Biol. 1998;122(1-2):139-48
9724615
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2446-51
16461894
J Physiol. 1991 Aug;439:701-15
1895247
J Cell Sci. 2008 Jun 1;121(11):1841-51
18477606
J Muscle Res Cell Motil. 2002;23(4):317-26
12630706
Trends Cell Biol. 2005 Sep;15(9):477-85
16061384
Cell Calcium. 2006 Sep;40(3):299-307
16765438
Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13385-90
18765796
Biophys J. 1995 Apr;68(4):1430-42
7787029
J Mol Biol. 2008 Dec 5;384(1):60-72
18817784
Circulation. 2007 Feb 13;115(6):743-51
17261657
Science. 2005 Jun 10;308(5728):1599-603
15802564
J Cell Biol. 2002 Apr 1;157(1):125-36
11927605
J Physiol (Paris). 1979;75(5):463-505
533865
J Biol Chem. 2002 Nov 22;277(47):44740-6
12237298
Am J Physiol Cell Physiol. 2000 Feb;278(2):C404-16
10666037
Biophys J. 2002 Mar;82(3):1338-44
11867450
Nature. 1998 Oct 29;395(6705):863-9
9804419
Circ Res. 2004 May 28;94(10):1279-89
15166115
Electrophoresis. 2003 Jun;24(11):1695-702
12783444
J Cell Biol. 2006 May 22;173(4):559-70
16702235
J Physiol. 2003 Oct 15;552(Pt 2):393-402
14561823
FASEB J. 2008 Aug;22(8):2912-9
18434434
Circ Res. 1992 May;70(5):865-84
1348975
Am J Physiol Cell Physiol. 2003 Dec;285(6):C1464-74
12917105
J Cell Sci. 2002 Dec 15;115(Pt 24):4925-36
12432079
J Gen Physiol. 1993 Feb;101(2):235-70
7681097
Am J Hum Genet. 2002 Sep;71(3):492-500
12145747
Am J Physiol Lung Cell Mol Physiol. 2006 Jan;290(1):L127-35
16113049
Adv Exp Med Biol. 2003;538:31-40; discussion 40-1
15098652
Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17519-24
16299103
J Muscle Res Cell Motil. 2005;26(2-3):135-41
16003463
Physiol Rev. 2000 Jul;80(3):1215-65
10893434
Science. 2001 Nov 23;294(5547):1704-8
11679633
J Mol Biol. 2007 Mar 16;367(1):36-41
17254601
Physiol Rev. 2000 Apr;80(2):853-924
10747208
Ann Neurol. 2003 Aug;54(2):248-51
12891679
Heart Fail Rev. 2005 Sep;10(3):175-85
16416041
EMBO J. 1992 May;11(5):1711-6
1582406
J Gen Physiol. 1991 Jun;97(6):1141-63
1678777
J Biol Chem. 2003 Feb 21;278(8):6059-65
12464612
J Biochem. 1986 May;99(5):1473-84
3754864
J Physiol. 2005 Apr 15;564(Pt 2):451-64
15731192
Circ Res. 2004 Feb 20;94(3):284-95
14976139
J Muscle Res Cell Motil. 2005;26(6-8):389-400
16477476
J Mol Biol. 2001 Mar 2;306(4):717-26
11243782
Proc R Soc Lond B Biol Sci. 1976 Mar 16;192(1109):451-61
4802
Biophys J. 2006 Jun 1;90(11):4119-27
16513777
Arch Biochem Biophys. 2006 Dec 15;456(2):216-23
16949549
Am J Physiol. 1994 Aug;267(2 Pt 1):C443-9
8074179