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Deficiency of smooth muscle myosin heavy chain isoform 2 increases muscle contractility and causes premature postnatal death in mice
Author(s) -
Chi Mei,
Zhou Yingbi,
Vedamoorthyrao Srikanth,
Liu Sumei,
Wood Jackie,
Periasamy Muthu
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.145
Subject(s) - contractility , myosin , endocrinology , medicine , gene isoform , biology , exon , muscle contraction , alternative splicing , myosin light chain kinase , contraction (grammar) , gene , microbiology and biotechnology , biochemistry
The heavy chains of smooth muscle myosin (SMHC) are motor proteins powering the muscle contraction. Alternate splicing of SMHC gene at the C‐terminus produces SM1, and SM2 isoforms. SM2 (200 kDa) contains a region of nine amino acids at C‐terminus, which is in contrast to a long non‐helical tail of 43 amino acids in the other isoform SM1 (204 kDa). During fetal development, SM2 appears in late fetal stage and increases steadily to reach the postnatal level. Decreased expression of SM2 has been found in tissues or organs associated with pathophysiological conditions, such as urinary obstruction, primary pulmonary hypertension, and aging. To unequivocally elucidate the role of SM2, we used an exon‐specific gene‐targeting strategy to generate a mouse model that was specifically deficient in SM2. Disruption of exon‐41 (SM2‐specific) of SMHC gene caused decrease (heterozygous; SM2 +/− ) or deficiency of SM2 (homozygous; SM2 −/− ) accompanied by concomitant down‐regulation of SM1 in bladders. While SM2 +/− mice were normal and healthy, SM2 −/− mice showed retarded growth, distention of bladder and alimentary tract, and development of hydronephrosis. All SM2 −/− mice died within 30 days of age. Isolated smooth muscle strips from infant SM2 −/− bladder (which showed normal morphology) exhibited increased contractility with unaltered rate of myosin light chain phosphorylation. Thus, in smooth muscle SM2 appears to function as an inhibitor to the contraction generated by SM1, and the loss of SM2 causes dysfunction of smooth muscle organs including the urinary tract, which leads to the development of hydronephrosis and premature postnatal death.