Reversal of impaired oxidative phosphorylation and calcium overloading in the skeletal muscle mitochondria of CHF-146 dystrophic hamsters

Syamal Bhattacharya, Patti L. Johnson, Jay H. Thakar

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Membrane-mediated excessive intracellular calcium accumulation (EICA) and diminished cellular energy production are the hallmarks of dystrophic pathobiology in Duchenne and Becker muscular dystrophies. We reported reversal of respiratory damage and Ca2+overloading in the in vitro cardiac mitochondria from CHF-146 dystrophic hamsters (DH) with hereditary muscular dystrophy (Bhattacharya et al., 1993). Here we studied respiratory dysfunctions in the skeletal muscle mitochondria from young and old DH, and whether these abnormalities can be reversed by reducing [Ca2+] in the isolation medium, thereby lowering intramitochondrial Ca2+-overloading. Age- and sex-matched CHF-148 albino normal hamsters (NH) served as controls. As an index of EICA and cellular degeneration, Ca and Mg levels were assayed in the skeletal muscle and mitochondria. Mitochondria from young and old DH, isolated without EDTA (B(o) medium), revealed poor coupling of oxidative phosphorylation, diminished stimulated oxygen consumption rate, and lower respiratory control ratio and ADP/O ratios, compared to NH. Incorporation of 10 mM EDTA (B(E) medium) in the isolation medium restored mitochondrial functions of the dystrophic organelles to a near-normal level, and reduced Ca2+-overloading. The mitochondrial Ca level in DH was significantly higher than in NH, irrespective of the medium. However, compared to B(o) medium, the dystrophic organelles isolated in BE medium had lower Ca levels and markedly improved oxidative phosphorylation as seen in NH. Muscle Ca contents in the young and old DH were elevated relative to NH, showing a positive correlation with the increased mitochondrial Ca2+-sequestration. Dystrophic muscle also revealed Ca deposition with an abundance of Ca2+-positive and necrotic myofibers by light microscopy, and intramitochondrial Ca2+-overloading by electron microscopy, respectively. However, Mg levels in the muscle and mitochondria did not alter with age or dystrophy. These data parallel our observations in the heart, and suggest that functional impairments and Ca2+-overloading also occur in the skeletal muscle mitochondria of DH, and are indeed reversible if EICA is regulated by slow Ca2+-channel blocker therapy (Johnson and Bhattacharya, 1993).

Original languageEnglish (US)
Pages (from-to)53-77
Number of pages25
JournalMolecular and Chemical Neuropathology
Volume34
Issue number1
DOIs
StatePublished - Jan 1 1998

Fingerprint

Muscle Mitochondrion
Oxidative Phosphorylation
Cricetinae
Skeletal Muscle
Calcium
Edetic Acid
Organelles
Mitochondria
Muscles
Duchenne Muscular Dystrophy
Muscular Dystrophies
Respiratory Rate
Oxygen Consumption
Adenosine Diphosphate
Microscopy
Electron Microscopy

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology

Cite this

Reversal of impaired oxidative phosphorylation and calcium overloading in the skeletal muscle mitochondria of CHF-146 dystrophic hamsters. / Bhattacharya, Syamal; Johnson, Patti L.; Thakar, Jay H.

In: Molecular and Chemical Neuropathology, Vol. 34, No. 1, 01.01.1998, p. 53-77.

Research output: Contribution to journalArticle

@article{f0243a5262c4461988035daf5589abdd,
title = "Reversal of impaired oxidative phosphorylation and calcium overloading in the skeletal muscle mitochondria of CHF-146 dystrophic hamsters",
abstract = "Membrane-mediated excessive intracellular calcium accumulation (EICA) and diminished cellular energy production are the hallmarks of dystrophic pathobiology in Duchenne and Becker muscular dystrophies. We reported reversal of respiratory damage and Ca2+overloading in the in vitro cardiac mitochondria from CHF-146 dystrophic hamsters (DH) with hereditary muscular dystrophy (Bhattacharya et al., 1993). Here we studied respiratory dysfunctions in the skeletal muscle mitochondria from young and old DH, and whether these abnormalities can be reversed by reducing [Ca2+] in the isolation medium, thereby lowering intramitochondrial Ca2+-overloading. Age- and sex-matched CHF-148 albino normal hamsters (NH) served as controls. As an index of EICA and cellular degeneration, Ca and Mg levels were assayed in the skeletal muscle and mitochondria. Mitochondria from young and old DH, isolated without EDTA (B(o) medium), revealed poor coupling of oxidative phosphorylation, diminished stimulated oxygen consumption rate, and lower respiratory control ratio and ADP/O ratios, compared to NH. Incorporation of 10 mM EDTA (B(E) medium) in the isolation medium restored mitochondrial functions of the dystrophic organelles to a near-normal level, and reduced Ca2+-overloading. The mitochondrial Ca level in DH was significantly higher than in NH, irrespective of the medium. However, compared to B(o) medium, the dystrophic organelles isolated in BE medium had lower Ca levels and markedly improved oxidative phosphorylation as seen in NH. Muscle Ca contents in the young and old DH were elevated relative to NH, showing a positive correlation with the increased mitochondrial Ca2+-sequestration. Dystrophic muscle also revealed Ca deposition with an abundance of Ca2+-positive and necrotic myofibers by light microscopy, and intramitochondrial Ca2+-overloading by electron microscopy, respectively. However, Mg levels in the muscle and mitochondria did not alter with age or dystrophy. These data parallel our observations in the heart, and suggest that functional impairments and Ca2+-overloading also occur in the skeletal muscle mitochondria of DH, and are indeed reversible if EICA is regulated by slow Ca2+-channel blocker therapy (Johnson and Bhattacharya, 1993).",
author = "Syamal Bhattacharya and Johnson, {Patti L.} and Thakar, {Jay H.}",
year = "1998",
month = "1",
day = "1",
doi = "10.1007/BF02815136",
language = "English (US)",
volume = "34",
pages = "53--77",
journal = "Journal of Molecular Neuroscience",
issn = "0895-8696",
publisher = "Humana Press",
number = "1",

}

TY - JOUR

T1 - Reversal of impaired oxidative phosphorylation and calcium overloading in the skeletal muscle mitochondria of CHF-146 dystrophic hamsters

AU - Bhattacharya, Syamal

AU - Johnson, Patti L.

AU - Thakar, Jay H.

PY - 1998/1/1

Y1 - 1998/1/1

N2 - Membrane-mediated excessive intracellular calcium accumulation (EICA) and diminished cellular energy production are the hallmarks of dystrophic pathobiology in Duchenne and Becker muscular dystrophies. We reported reversal of respiratory damage and Ca2+overloading in the in vitro cardiac mitochondria from CHF-146 dystrophic hamsters (DH) with hereditary muscular dystrophy (Bhattacharya et al., 1993). Here we studied respiratory dysfunctions in the skeletal muscle mitochondria from young and old DH, and whether these abnormalities can be reversed by reducing [Ca2+] in the isolation medium, thereby lowering intramitochondrial Ca2+-overloading. Age- and sex-matched CHF-148 albino normal hamsters (NH) served as controls. As an index of EICA and cellular degeneration, Ca and Mg levels were assayed in the skeletal muscle and mitochondria. Mitochondria from young and old DH, isolated without EDTA (B(o) medium), revealed poor coupling of oxidative phosphorylation, diminished stimulated oxygen consumption rate, and lower respiratory control ratio and ADP/O ratios, compared to NH. Incorporation of 10 mM EDTA (B(E) medium) in the isolation medium restored mitochondrial functions of the dystrophic organelles to a near-normal level, and reduced Ca2+-overloading. The mitochondrial Ca level in DH was significantly higher than in NH, irrespective of the medium. However, compared to B(o) medium, the dystrophic organelles isolated in BE medium had lower Ca levels and markedly improved oxidative phosphorylation as seen in NH. Muscle Ca contents in the young and old DH were elevated relative to NH, showing a positive correlation with the increased mitochondrial Ca2+-sequestration. Dystrophic muscle also revealed Ca deposition with an abundance of Ca2+-positive and necrotic myofibers by light microscopy, and intramitochondrial Ca2+-overloading by electron microscopy, respectively. However, Mg levels in the muscle and mitochondria did not alter with age or dystrophy. These data parallel our observations in the heart, and suggest that functional impairments and Ca2+-overloading also occur in the skeletal muscle mitochondria of DH, and are indeed reversible if EICA is regulated by slow Ca2+-channel blocker therapy (Johnson and Bhattacharya, 1993).

AB - Membrane-mediated excessive intracellular calcium accumulation (EICA) and diminished cellular energy production are the hallmarks of dystrophic pathobiology in Duchenne and Becker muscular dystrophies. We reported reversal of respiratory damage and Ca2+overloading in the in vitro cardiac mitochondria from CHF-146 dystrophic hamsters (DH) with hereditary muscular dystrophy (Bhattacharya et al., 1993). Here we studied respiratory dysfunctions in the skeletal muscle mitochondria from young and old DH, and whether these abnormalities can be reversed by reducing [Ca2+] in the isolation medium, thereby lowering intramitochondrial Ca2+-overloading. Age- and sex-matched CHF-148 albino normal hamsters (NH) served as controls. As an index of EICA and cellular degeneration, Ca and Mg levels were assayed in the skeletal muscle and mitochondria. Mitochondria from young and old DH, isolated without EDTA (B(o) medium), revealed poor coupling of oxidative phosphorylation, diminished stimulated oxygen consumption rate, and lower respiratory control ratio and ADP/O ratios, compared to NH. Incorporation of 10 mM EDTA (B(E) medium) in the isolation medium restored mitochondrial functions of the dystrophic organelles to a near-normal level, and reduced Ca2+-overloading. The mitochondrial Ca level in DH was significantly higher than in NH, irrespective of the medium. However, compared to B(o) medium, the dystrophic organelles isolated in BE medium had lower Ca levels and markedly improved oxidative phosphorylation as seen in NH. Muscle Ca contents in the young and old DH were elevated relative to NH, showing a positive correlation with the increased mitochondrial Ca2+-sequestration. Dystrophic muscle also revealed Ca deposition with an abundance of Ca2+-positive and necrotic myofibers by light microscopy, and intramitochondrial Ca2+-overloading by electron microscopy, respectively. However, Mg levels in the muscle and mitochondria did not alter with age or dystrophy. These data parallel our observations in the heart, and suggest that functional impairments and Ca2+-overloading also occur in the skeletal muscle mitochondria of DH, and are indeed reversible if EICA is regulated by slow Ca2+-channel blocker therapy (Johnson and Bhattacharya, 1993).

UR - http://www.scopus.com/inward/record.url?scp=0031681377&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031681377&partnerID=8YFLogxK

U2 - 10.1007/BF02815136

DO - 10.1007/BF02815136

M3 - Article

VL - 34

SP - 53

EP - 77

JO - Journal of Molecular Neuroscience

JF - Journal of Molecular Neuroscience

SN - 0895-8696

IS - 1

ER -