Exercise reverses preamyloid oligomer and prolongs survival in αB-crystallin-based desmin-related cardiomyopathy

Alina Maloyan, James Gulick, Charles G. Glabe, Rakez Kayed, Jeffrey Robbins

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

The R120G mutation in the small heat shock-like protein αB-crystallin (CryABR120G) causes desmin-related myopathy (DRM), which is characterized by the formation of desmin- and CryAB-containing aggregates within muscle fibers. Mice with cardiac-specific overexpression of CryAB R120G develop cardiomyopathy at 3 months and die at 6-7 months from heart failure (HF). Previous studies showed that overexpression of CryAB R120G results in accumulation of preamyloid oligomer (PAO). PAO is considered to be the cytotoxic entity in many of the protein misfolding-based neurodegenerative diseases. On the basis of data from mouse models of neurodegenerative diseases showing that exercise or environmental enrichment reduces the amyloid oligomer level and improves cognitive ability, we hypothesized that CryABR120G-induced DRM would also respond favorably to prolonged voluntary exercise, reducing HF symptoms and rescuing the mice from premature death. Six months of voluntary exercise in CryABR120G animals resulted in 100% survival at a time when all unexercised mice had died. After 22 weeks of exercise, PAO levels were decreased by 47% compared with the unexercised CryABR120G control mice (P = 0.00001). Although CryABR120G expression led to decreased levels of the metallomembrane endopeptidase neprilysin, normal levels were maintained in the exercised CryABR120G mice, and in vitro loss-of-function and gain-of-function experiments using adenovirus-infected cardiomyocytes confirmed the importance of neprilysin in ameliorating PAO accumulation. The data demonstrate that voluntary exercise slows the progression to HF in the CryABR120G DRM model and that PAO accumulation is mediated, at least in part, by decreased neprilysin activity.

Original languageEnglish (US)
Pages (from-to)5995-6000
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number14
DOIs
StatePublished - Apr 3 2007
Externally publishedYes

Fingerprint

Crystallins
Desmin
Cardiomyopathies
Neprilysin
Heart Failure
Neurodegenerative Diseases
Small Heat-Shock Proteins
Endopeptidases
Premature Mortality
Amyloid
Cardiac Myocytes
Adenoviridae
Muscles
Mutation
Myopathy, Myofibrillar, Desmin-Related
Proteins

Keywords

  • Cardiac
  • Disease
  • Heart
  • Transgenic

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Exercise reverses preamyloid oligomer and prolongs survival in αB-crystallin-based desmin-related cardiomyopathy. / Maloyan, Alina; Gulick, James; Glabe, Charles G.; Kayed, Rakez; Robbins, Jeffrey.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 14, 03.04.2007, p. 5995-6000.

Research output: Contribution to journalArticle

@article{810a94fb8b5042fe8cb5b6aaca47cf51,
title = "Exercise reverses preamyloid oligomer and prolongs survival in αB-crystallin-based desmin-related cardiomyopathy",
abstract = "The R120G mutation in the small heat shock-like protein αB-crystallin (CryABR120G) causes desmin-related myopathy (DRM), which is characterized by the formation of desmin- and CryAB-containing aggregates within muscle fibers. Mice with cardiac-specific overexpression of CryAB R120G develop cardiomyopathy at 3 months and die at 6-7 months from heart failure (HF). Previous studies showed that overexpression of CryAB R120G results in accumulation of preamyloid oligomer (PAO). PAO is considered to be the cytotoxic entity in many of the protein misfolding-based neurodegenerative diseases. On the basis of data from mouse models of neurodegenerative diseases showing that exercise or environmental enrichment reduces the amyloid oligomer level and improves cognitive ability, we hypothesized that CryABR120G-induced DRM would also respond favorably to prolonged voluntary exercise, reducing HF symptoms and rescuing the mice from premature death. Six months of voluntary exercise in CryABR120G animals resulted in 100{\%} survival at a time when all unexercised mice had died. After 22 weeks of exercise, PAO levels were decreased by 47{\%} compared with the unexercised CryABR120G control mice (P = 0.00001). Although CryABR120G expression led to decreased levels of the metallomembrane endopeptidase neprilysin, normal levels were maintained in the exercised CryABR120G mice, and in vitro loss-of-function and gain-of-function experiments using adenovirus-infected cardiomyocytes confirmed the importance of neprilysin in ameliorating PAO accumulation. The data demonstrate that voluntary exercise slows the progression to HF in the CryABR120G DRM model and that PAO accumulation is mediated, at least in part, by decreased neprilysin activity.",
keywords = "Cardiac, Disease, Heart, Transgenic",
author = "Alina Maloyan and James Gulick and Glabe, {Charles G.} and Rakez Kayed and Jeffrey Robbins",
year = "2007",
month = "4",
day = "3",
doi = "10.1073/pnas.0609202104",
language = "English (US)",
volume = "104",
pages = "5995--6000",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "14",

}

TY - JOUR

T1 - Exercise reverses preamyloid oligomer and prolongs survival in αB-crystallin-based desmin-related cardiomyopathy

AU - Maloyan, Alina

AU - Gulick, James

AU - Glabe, Charles G.

AU - Kayed, Rakez

AU - Robbins, Jeffrey

PY - 2007/4/3

Y1 - 2007/4/3

N2 - The R120G mutation in the small heat shock-like protein αB-crystallin (CryABR120G) causes desmin-related myopathy (DRM), which is characterized by the formation of desmin- and CryAB-containing aggregates within muscle fibers. Mice with cardiac-specific overexpression of CryAB R120G develop cardiomyopathy at 3 months and die at 6-7 months from heart failure (HF). Previous studies showed that overexpression of CryAB R120G results in accumulation of preamyloid oligomer (PAO). PAO is considered to be the cytotoxic entity in many of the protein misfolding-based neurodegenerative diseases. On the basis of data from mouse models of neurodegenerative diseases showing that exercise or environmental enrichment reduces the amyloid oligomer level and improves cognitive ability, we hypothesized that CryABR120G-induced DRM would also respond favorably to prolonged voluntary exercise, reducing HF symptoms and rescuing the mice from premature death. Six months of voluntary exercise in CryABR120G animals resulted in 100% survival at a time when all unexercised mice had died. After 22 weeks of exercise, PAO levels were decreased by 47% compared with the unexercised CryABR120G control mice (P = 0.00001). Although CryABR120G expression led to decreased levels of the metallomembrane endopeptidase neprilysin, normal levels were maintained in the exercised CryABR120G mice, and in vitro loss-of-function and gain-of-function experiments using adenovirus-infected cardiomyocytes confirmed the importance of neprilysin in ameliorating PAO accumulation. The data demonstrate that voluntary exercise slows the progression to HF in the CryABR120G DRM model and that PAO accumulation is mediated, at least in part, by decreased neprilysin activity.

AB - The R120G mutation in the small heat shock-like protein αB-crystallin (CryABR120G) causes desmin-related myopathy (DRM), which is characterized by the formation of desmin- and CryAB-containing aggregates within muscle fibers. Mice with cardiac-specific overexpression of CryAB R120G develop cardiomyopathy at 3 months and die at 6-7 months from heart failure (HF). Previous studies showed that overexpression of CryAB R120G results in accumulation of preamyloid oligomer (PAO). PAO is considered to be the cytotoxic entity in many of the protein misfolding-based neurodegenerative diseases. On the basis of data from mouse models of neurodegenerative diseases showing that exercise or environmental enrichment reduces the amyloid oligomer level and improves cognitive ability, we hypothesized that CryABR120G-induced DRM would also respond favorably to prolonged voluntary exercise, reducing HF symptoms and rescuing the mice from premature death. Six months of voluntary exercise in CryABR120G animals resulted in 100% survival at a time when all unexercised mice had died. After 22 weeks of exercise, PAO levels were decreased by 47% compared with the unexercised CryABR120G control mice (P = 0.00001). Although CryABR120G expression led to decreased levels of the metallomembrane endopeptidase neprilysin, normal levels were maintained in the exercised CryABR120G mice, and in vitro loss-of-function and gain-of-function experiments using adenovirus-infected cardiomyocytes confirmed the importance of neprilysin in ameliorating PAO accumulation. The data demonstrate that voluntary exercise slows the progression to HF in the CryABR120G DRM model and that PAO accumulation is mediated, at least in part, by decreased neprilysin activity.

KW - Cardiac

KW - Disease

KW - Heart

KW - Transgenic

UR - http://www.scopus.com/inward/record.url?scp=34347249232&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34347249232&partnerID=8YFLogxK

U2 - 10.1073/pnas.0609202104

DO - 10.1073/pnas.0609202104

M3 - Article

C2 - 17389375

AN - SCOPUS:34347249232

VL - 104

SP - 5995

EP - 6000

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

SN - 0027-8424

IS - 14

ER -