Transgenic remodeling of the regulatory myosin light chains in the mammalian heart

James Gulick, Timothy Hewett, Raisa Klevitsky, Scott H. Buck, Richard L. Moss, Jeffrey Robbins

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

The regulatory myosin light chain (MLC) regulates contraction in smooth muscle. However, its function in striated muscle remains obscure, and the different functional activities of the various isoforms that are expressed in the mammalian heart (ventricle- and atrium-specific MLC2) remain undefined. To begin to explore these issues, we used transgenesis to determine the feasibility of effecting a complete or partial replacement of the cardiac regulatory light chains with the isoform that is normally expressed in fast skeletal muscle fibers (fast muscle-specific MLC2). Multiple lines of transgenic mice were generated that expressed the transgene at varying levels in the heart in a copy number-dependent fashion. There is a major discordance in the manner in which the different cardiac compartments respond to high levels of overexpression of the transgene. In atria, isoform replacement with the skeletal protein was quite efficient, even at low copy number. The ventricle is much more refractory to replacement, and despite high levels of transgenic transcript, protein replacement was incomplete. Replacement could be further increased by breeding the transgenic lines with one another. Despite very high levels of transgenic transcript in these mice, the overall level of the regulatory light chain in both compartments remained essentially constant; only the protein isoform ratios were altered. The partial replacement of the ventricular with the skeletal isoform reduced both left ventricular contractility and relaxation, although the unloaded shortening velocity of isolated ventricular cardiomyocytes was not significantly different.

Original languageEnglish (US)
Pages (from-to)655-664
Number of pages10
JournalCirculation Research
Volume80
Issue number5
StatePublished - 1997
Externally publishedYes

Fingerprint

Myosin Light Chains
Protein Isoforms
Transgenes
Light
Gene Transfer Techniques
Striated Muscle
Skeletal Muscle Fibers
Heart Atria
Cardiac Myocytes
Transgenic Mice
Heart Ventricles
Breeding
Smooth Muscle
Proteins
Muscles

Keywords

  • gene
  • muscle
  • myosin light chain
  • transgene

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Gulick, J., Hewett, T., Klevitsky, R., Buck, S. H., Moss, R. L., & Robbins, J. (1997). Transgenic remodeling of the regulatory myosin light chains in the mammalian heart. Circulation Research, 80(5), 655-664.

Transgenic remodeling of the regulatory myosin light chains in the mammalian heart. / Gulick, James; Hewett, Timothy; Klevitsky, Raisa; Buck, Scott H.; Moss, Richard L.; Robbins, Jeffrey.

In: Circulation Research, Vol. 80, No. 5, 1997, p. 655-664.

Research output: Contribution to journalArticle

Gulick, J, Hewett, T, Klevitsky, R, Buck, SH, Moss, RL & Robbins, J 1997, 'Transgenic remodeling of the regulatory myosin light chains in the mammalian heart', Circulation Research, vol. 80, no. 5, pp. 655-664.
Gulick J, Hewett T, Klevitsky R, Buck SH, Moss RL, Robbins J. Transgenic remodeling of the regulatory myosin light chains in the mammalian heart. Circulation Research. 1997;80(5):655-664.
Gulick, James ; Hewett, Timothy ; Klevitsky, Raisa ; Buck, Scott H. ; Moss, Richard L. ; Robbins, Jeffrey. / Transgenic remodeling of the regulatory myosin light chains in the mammalian heart. In: Circulation Research. 1997 ; Vol. 80, No. 5. pp. 655-664.
@article{1fbb87b2552547d099b6fdd7f38cc2a7,
title = "Transgenic remodeling of the regulatory myosin light chains in the mammalian heart",
abstract = "The regulatory myosin light chain (MLC) regulates contraction in smooth muscle. However, its function in striated muscle remains obscure, and the different functional activities of the various isoforms that are expressed in the mammalian heart (ventricle- and atrium-specific MLC2) remain undefined. To begin to explore these issues, we used transgenesis to determine the feasibility of effecting a complete or partial replacement of the cardiac regulatory light chains with the isoform that is normally expressed in fast skeletal muscle fibers (fast muscle-specific MLC2). Multiple lines of transgenic mice were generated that expressed the transgene at varying levels in the heart in a copy number-dependent fashion. There is a major discordance in the manner in which the different cardiac compartments respond to high levels of overexpression of the transgene. In atria, isoform replacement with the skeletal protein was quite efficient, even at low copy number. The ventricle is much more refractory to replacement, and despite high levels of transgenic transcript, protein replacement was incomplete. Replacement could be further increased by breeding the transgenic lines with one another. Despite very high levels of transgenic transcript in these mice, the overall level of the regulatory light chain in both compartments remained essentially constant; only the protein isoform ratios were altered. The partial replacement of the ventricular with the skeletal isoform reduced both left ventricular contractility and relaxation, although the unloaded shortening velocity of isolated ventricular cardiomyocytes was not significantly different.",
keywords = "gene, muscle, myosin light chain, transgene",
author = "James Gulick and Timothy Hewett and Raisa Klevitsky and Buck, {Scott H.} and Moss, {Richard L.} and Jeffrey Robbins",
year = "1997",
language = "English (US)",
volume = "80",
pages = "655--664",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "5",

}

TY - JOUR

T1 - Transgenic remodeling of the regulatory myosin light chains in the mammalian heart

AU - Gulick, James

AU - Hewett, Timothy

AU - Klevitsky, Raisa

AU - Buck, Scott H.

AU - Moss, Richard L.

AU - Robbins, Jeffrey

PY - 1997

Y1 - 1997

N2 - The regulatory myosin light chain (MLC) regulates contraction in smooth muscle. However, its function in striated muscle remains obscure, and the different functional activities of the various isoforms that are expressed in the mammalian heart (ventricle- and atrium-specific MLC2) remain undefined. To begin to explore these issues, we used transgenesis to determine the feasibility of effecting a complete or partial replacement of the cardiac regulatory light chains with the isoform that is normally expressed in fast skeletal muscle fibers (fast muscle-specific MLC2). Multiple lines of transgenic mice were generated that expressed the transgene at varying levels in the heart in a copy number-dependent fashion. There is a major discordance in the manner in which the different cardiac compartments respond to high levels of overexpression of the transgene. In atria, isoform replacement with the skeletal protein was quite efficient, even at low copy number. The ventricle is much more refractory to replacement, and despite high levels of transgenic transcript, protein replacement was incomplete. Replacement could be further increased by breeding the transgenic lines with one another. Despite very high levels of transgenic transcript in these mice, the overall level of the regulatory light chain in both compartments remained essentially constant; only the protein isoform ratios were altered. The partial replacement of the ventricular with the skeletal isoform reduced both left ventricular contractility and relaxation, although the unloaded shortening velocity of isolated ventricular cardiomyocytes was not significantly different.

AB - The regulatory myosin light chain (MLC) regulates contraction in smooth muscle. However, its function in striated muscle remains obscure, and the different functional activities of the various isoforms that are expressed in the mammalian heart (ventricle- and atrium-specific MLC2) remain undefined. To begin to explore these issues, we used transgenesis to determine the feasibility of effecting a complete or partial replacement of the cardiac regulatory light chains with the isoform that is normally expressed in fast skeletal muscle fibers (fast muscle-specific MLC2). Multiple lines of transgenic mice were generated that expressed the transgene at varying levels in the heart in a copy number-dependent fashion. There is a major discordance in the manner in which the different cardiac compartments respond to high levels of overexpression of the transgene. In atria, isoform replacement with the skeletal protein was quite efficient, even at low copy number. The ventricle is much more refractory to replacement, and despite high levels of transgenic transcript, protein replacement was incomplete. Replacement could be further increased by breeding the transgenic lines with one another. Despite very high levels of transgenic transcript in these mice, the overall level of the regulatory light chain in both compartments remained essentially constant; only the protein isoform ratios were altered. The partial replacement of the ventricular with the skeletal isoform reduced both left ventricular contractility and relaxation, although the unloaded shortening velocity of isolated ventricular cardiomyocytes was not significantly different.

KW - gene

KW - muscle

KW - myosin light chain

KW - transgene

UR - http://www.scopus.com/inward/record.url?scp=0030892526&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030892526&partnerID=8YFLogxK

M3 - Article

C2 - 9130446

AN - SCOPUS:0030892526

VL - 80

SP - 655

EP - 664

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 5

ER -