Loss of Prox1 in striated muscle causes slow to fast skeletal muscle fiber conversion and dilated cardiomyopathy

TY - JOUR

T1 - Loss of Prox1 in striated muscle causes slow to fast skeletal muscle fiber conversion and dilated cardiomyopathy

AU - Petchey, Louisa K.

AU - Risebro, Catherine A.

AU - Vieira, Joaquim M.

AU - Roberts, Tom

AU - Bryson, John B.

AU - Greensmith, Linda

AU - Lythgoe, Mark F.

AU - Riley, Paul R.

PY - 2014/7/1

Y1 - 2014/7/1

N2 - Correct regulation of troponin and myosin contractile protein gene isoforms is a critical determinant of cardiac and skeletal striated muscle development and function, with misexpression frequently associated with impaired contractility or disease. Here we reveal a novel requirement for Prospero-related homeobox factor 1 (Prox1) during mouse heart development in the direct transcriptional repression of the fast-twitch skeletal muscle genes troponin T3, troponin I2, and myosin light chain 1. A proportion of cardiacspecific Prox1 knockout mice survive beyond birth with hearts characterized by marked overexpression of fast-twitch genes and postnatal development of a fatal dilated cardiomyopathy. Through conditional knockout of Prox1 from skeletal muscle, we demonstrate a conserved requirement for Prox1 in the repression of troponin T3, troponin I2, andmyosin light chain 1 between cardiac and slow-twitch skeletal muscle and establish Prox1 ablation as sufficient to cause a switch from a slow- to fast-twitch muscle phenotype. Our study identifies conserved roles for Prox1 between cardiac and skeletal muscle, specifically implicated in slow-twitch fiber-type specification, function, and cardiomyopathic disease.

AB - Correct regulation of troponin and myosin contractile protein gene isoforms is a critical determinant of cardiac and skeletal striated muscle development and function, with misexpression frequently associated with impaired contractility or disease. Here we reveal a novel requirement for Prospero-related homeobox factor 1 (Prox1) during mouse heart development in the direct transcriptional repression of the fast-twitch skeletal muscle genes troponin T3, troponin I2, and myosin light chain 1. A proportion of cardiacspecific Prox1 knockout mice survive beyond birth with hearts characterized by marked overexpression of fast-twitch genes and postnatal development of a fatal dilated cardiomyopathy. Through conditional knockout of Prox1 from skeletal muscle, we demonstrate a conserved requirement for Prox1 in the repression of troponin T3, troponin I2, andmyosin light chain 1 between cardiac and slow-twitch skeletal muscle and establish Prox1 ablation as sufficient to cause a switch from a slow- to fast-twitch muscle phenotype. Our study identifies conserved roles for Prox1 between cardiac and skeletal muscle, specifically implicated in slow-twitch fiber-type specification, function, and cardiomyopathic disease.

KW - Animals

KW - Cardiomyopathy, Dilated/metabolism

KW - Cell Differentiation/physiology

KW - Chromatin Immunoprecipitation

KW - DNA Primers/genetics

KW - Fluorescent Antibody Technique

KW - Gene Expression Regulation, Developmental/physiology

KW - Homeodomain Proteins/genetics

KW - Mice

KW - Mice, Knockout

KW - Microarray Analysis

KW - Muscle, Striated/embryology

KW - Myocardium/metabolism

KW - Myosin Light Chains/metabolism

KW - Real-Time Polymerase Chain Reaction

KW - Troponin/metabolism

KW - Troponin I/metabolism

KW - Tumor Suppressor Proteins/deficiency

UR - http://www.scopus.com/inward/record.url?scp=84903748882&partnerID=8YFLogxK

U2 - 10.1073/pnas.1406191111

DO - 10.1073/pnas.1406191111

M3 - Article

C2 - 24938781

SN - 0027-8424

VL - 111

SP - 9515

EP - 9520

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 26

ER -