Lamin A N-terminal phosphorylation is associated with myoblast activation: impairment in Emery-Dreifuss muscular dystrophy.
BACKGROUND
Skeletal muscle disorders associated with mutations of lamin A/C gene include autosomal Emery-Dreifuss muscular dystrophy and limb girdle muscular dystrophy 1B. The pathogenic mechanism underlying these diseases is unknown. Recent data suggest an impairment of signalling mechanisms as a possible cause of muscle malfunction. A molecular complex in muscle cells formed by lamin A/C, emerin, and nuclear actin has been identified. The stability of this protein complex appears to be related to phosphorylation mechanisms.


OBJECTIVE
To analyse lamin A/C phosphorylation in control and laminopathic muscle cells.


METHODS
Lamin A/C N-terminal phosphorylation was determined in cultured mouse myoblasts using a specific antibody. Insulin treatment of serum starved myoblast cultures was carried out to evaluate involvement of insulin signalling in the phosphorylation pathway. Screening of four Emery-Dreifuss and one limb girdle muscular dystrophy 1B cases was undertaken to investigate lamin A/C phosphorylation in both cultured myoblasts and mature muscle fibres.


RESULTS
Phosphorylation of lamin A was observed during myoblast differentiation or proliferation, along with reduced lamin A/C phosphorylation in quiescent myoblasts. Lamin A N-terminus phosphorylation was induced by an insulin stimulus, which conversely did not affect lamin C phosphorylation. Lamin A/C was also hyperphosphorylated in mature muscle, mostly in regenerating fibres. Lamin A/C phosphorylation was strikingly reduced in laminopathic myoblasts and muscle fibres, while it was preserved in interstitial fibroblasts.


CONCLUSIONS
Altered lamin A/C interplay with a muscle specific phosphorylation partner might be involved in the pathogenic mechanism of Emery-Dreifuss muscular dystrophy and limb girdle muscular dystrophy 1B.
Cenni
V
V
ITOI, CNR, Unit of Bologna, c/o IOR, Bologna, Italy.
Sabatelli
P
P
Mattioli
E
E
Marmiroli
S
S
Capanni
C
C
Ognibene
A
A
Squarzoni
S
S
Maraldi
N M
NM
Bonne
G
G
Columbaro
M
M
Merlini
L
L
Lattanzi
G
G
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D006801:Humans; D007328:Insulin / Q000378:metabolism; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics / Q000378:metabolism*; D032446:Myoblasts / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction
D007328:Insulin; C494847:LMNA protein, human; D034904:Lamin Type A
Nature. 2003 May 15;423(6937):293-8
12714972
Science. 2002 Aug 2;297(5582):854-7
12161659
J Hum Genet. 2003;48(5):271-4
12768443
Curr Opin Cell Biol. 2003 Jun;15(3):358-66
12787780
J Cell Sci. 2003 Jul 15;116(Pt 14):3027-35
12783988
Science. 2003 Jun 27;300(5628):2055
12702809
Lancet. 2003 Aug 9;362(9382):440-5
12927431
Trends Mol Med. 2003 Sep;9(9):370-5
13129702
Cell Mol Life Sci. 2003 Oct;60(10):2053-63
14618255
Mol Cell Biol. 2004 Feb;24(4):1481-92
14749366
J Biol Chem. 2004 Mar 26;279(13):13265-71
14718546
J Biol Chem. 1988 Jan 25;263(3):1103-6
3275664
Eur J Cell Biol. 1991 Apr;54(2):299-304
1652444
Nat Genet. 1994 Dec;8(4):323-7
7894480
N Engl J Med. 1999 Dec 2;341(23):1715-24
10580070
J Cell Biol. 1999 Nov 29;147(5):913-20
10579712
Nat Genet. 2000 Feb;24(2):153-6
10655060
Am J Hum Genet. 2000 Apr;66(4):1407-12
10739764
Hum Mol Genet. 2000 May 22;9(9):1453-9
10814726
Neuromuscul Disord. 2000 Jun;10(4-5):228-32
10838246
Ann Neurol. 2000 Aug;48(2):170-80
10939567
Mol Biol Cell. 2000 Sep;11(9):3089-99
10982402
Differentiation. 2000 Dec;66(4-5):208-17
11269947
Muscle Nerve. 2001 Jun;24(6):826-9
11360268
Cell Mol Life Sci. 2001 Nov;58(12-13):1781-9
11766879
Am J Hum Genet. 2002 Mar;70(3):726-36
11799477
J Am Coll Cardiol. 2002 Mar 20;39(6):981-90
11897440
Structure. 2002 Jun;10(6):811-23
12057196
Am J Hum Genet. 2002 Aug;71(2):426-31
12075506
J Cell Biochem. 2002;86(2):320-30
12112001
Adv Enzyme Regul. 2002;42:1-18
12123703
Neurology. 2002 Aug 27;59(4):620-3
12196663
Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13049-54
12235369
Neuromuscul Disord. 2002 Nov;12(9):815-23
12398831
Nat Rev Mol Cell Biol. 2002 Nov;3(11):848-58
12415302
J Cell Biol. 2002 Dec 9;159(5):783-93
12473687
J Biol Chem. 2003 Feb 28;278(9):6969-75
12493765
Biochem Biophys Res Commun. 2003 Apr 11;303(3):764-70
12670476
Stroke. 2003 Apr;34(4):901-8
12649505
Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4598-603
12684533
Biochemistry. 2003 May 6;42(17):4819-28
12718522
Exp Cell Res. 2003 May 15;286(1):75-86
12729796
J Cell Biochem. 1996 Jul;62(1):76-89
8964790
FEBS Lett. 1998 Apr 3;425(3):485-9
9563518
Nat Genet. 1999 Mar;21(3):285-8
10080180
Biochim Biophys Acta. 2003 May 20;1638(1):57-62
12757935