Aging-associated Deletions of Human Diaphragmatic Mitochondrial DNA

Torii, Keizo; Sugiyama, Satoru; Tanaka, Masashi; Takagi, Kenzo; Hanaki, Yoshihiro; Iida, Kunihiro; Matsuyama, Mutsumi; Hirabayashi, Norio; Uno, Yutaka; Ozawa, Takayuki

doi:10.1165/ajrcmb/6.5.543

Cited by 46 publications

(15 citation statements)

References 18 publications

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“…Aging increases mitochondrial DNA deletions in human diaphragm [159]. The pattern of mitochondrial DNA mutation is consistent with, and possibly a cause of, decreases in the activity of electron transport chain complexes I and IV found in the diaphragm of old rats [160].…”

Section: Cellular Mediators Of Diaphragm Abnormalities In Chfmentioning

confidence: 61%

Diaphragm abnormalities in heart failure and aging: mechanisms and integration of cardiovascular and respiratory pathophysiology

Kelley

Ferreira

2016

Heart Fail Rev

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Inspiratory function is essential for alveolar ventilation and expulsive behaviors that promote airway clearance (e.g., coughing and sneezing). Current evidence demonstrates that inspiratory dysfunction occurs during healthy aging and is accentuated by chronic heart failure (CHF). This inspiratory dysfunction contributes to key aspects of CHF and aging cardiovascular and pulmonary pathophysiology including: i) impaired airway clearance and predisposition to pneumonia; ii) inability to sustain ventilation during physical activity; iii) shallow breathing pattern that limits alveolar ventilation and gas exchange; and iv) sympathetic activation that causes cardiac arrhythmias and tissue vasoconstriction. The diaphragm is the primary inspiratory muscle, hence, its neuromuscular integrity is a main determinant of the adequacy of inspiratory function. Mechanistic work within animal and cellular models has revealed specific factors that may be responsible for diaphragm neuromuscular abnormalities in CHF and aging. These include phrenic nerve and neuromuscular junction alterations as well as intrinsic myocyte abnormalities, such as changes in the quantity and quality of contractile proteins, accelerated fiber atrophy, and shifts in fiber type distribution. CHF, aging, or CHF in the presence of aging disturbs the dynamics of circulating factors (e.g., cytokines and angiotensin II) and cell signaling involving sphingolipids, reactive oxygen species, and proteolytic pathways, thus leading to the previously listed abnormalities. Exercise-based rehabilitation combined with pharmacological therapies targeting the pathways reviewed herein hold promise to treat diaphragm abnormalities and inspiratory muscle dysfunction in CHF and aging.

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Section: Cellular Mediators Of Diaphragm Abnormalities In Chfmentioning

confidence: 61%

Diaphragm abnormalities in heart failure and aging: mechanisms and integration of cardiovascular and respiratory pathophysiology

Kelley

Ferreira

2016

Heart Fail Rev

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“…Subjects with sarcopenia had a unique deletion in the mitochondrially encoded ND5 region (12175–13708 bp), which is a hotspot for mtDNA deletions and is associated with disease states 27;28 and aging. 29 Interestingly, aged human muscles are reported to have a higher mtDNA/nuclear DNA ratio than young, suggesting that cells may attempt to compensate for an inefficient ATP production per mitochondrion by up-regulating respiratory enzymes. 11;30 The mitochondrial genome undergoes continuous turnover with dynamic replication and replacement with a half life of a few weeks.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA deletion and sarcopenia

Shah¹,

Scariano²,

Waters³

et al. 2009

Genetics in Medicine

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Purpose Accumulation of mitochondrial DNA (mtDNA) deletions and the resultant impaired oxidative phosphorylation may play a pathogenic role in the mediation of age-related sarcopenia. Methods Twenty four participants of the New Mexico Aging Process Study were classified as normal lean (n=15) or sarcopenic (n=9) based on body composition determined by Dual Energy X-ray Absorptiometry. Complex I and IV activities were measured in the skeletal muscle samples obtained from gastrocnemius muscle. A two-stage nested PCR strategy was used to identify the mtDNA deletions in the entire mitochondrial genome in the skeletal muscle samples. Results While complex I activity was not significantly different (5.5 ± 0.9 vs. 4.6 ± 0.7 mU/mg protein, p>0.05), complex IV activity was higher in sarcopenic subjects (1.4 ± 0.3 vs. 1.0 ± 0.1 mU/mg protein, p<0.05). mtDNA deletions were mostly located in the region of complex I and spanned from NADH dehydrogenase (ND)1 to ND6. Deletions in the 8577–10407 bp and 10233–11249 bp regions were associated with a significant decrease in complex I activity (p<0.05 and p=0.02 respectively). Total cumulative deletion, defined as the sum of individual length of deletions in a subject, was comparable in subjects with and without sarcopenia (1760 ± 726 vs. 1782 ± 888 bp, p>0.05). The magnitude of mtDNA deletion, however, correlated positively with lean body mass (r=0.43, p<0.05). Conclusion Thus, mtDNA deletions are common in elderly subjects and are negatively related to complex I activity. The positive association between mtDNA deletions and lean body mass needs to be confirmed by studies in a larger study population.

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“…Muscle biopsy specimens from 8 patients (59-73 years; mean, 67 years) with IBM, and from 10 young (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38) years; mean, 30 years) and 9 older (59-78 years; mean, 66 years) patients with PM or D M were examined. The biopsy (16 needle, 11 open) specimens were obtained from the quadriceps muscle in 13 patients, the biceps in 11 patients, and the deltoid in 3 patients.…”

Section: Methodsmentioning

confidence: 99%

Ragged Red Fibers in Normal Aging and Inflammatory Myopathy

Rifai

Welle

Kamp

et al. 1995

Annals of Neurology

140

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Ragged red fibers are an important marker for mitochondrial disease. To evaluate the hypothesis that mitochondrial dysfunction may play a role in the pathogenesis of aging and inclusion body myositis, we studied the frequency of ragged red fibers in muscle biopsy specimens from 15 young and 13 old normal adults, and from 27 patients with inclusion body myositis, polymyositis, or dermatomyositis. Serial transverse cryostat sections were stained with modified Gomori trichrome, modified succinic dehydrogenase, and cytochrome c oxidase. The frequency of ragged red fibers, determined by measuring the percent number of succinic dehydrogenase-positive ragged red fiber equivalents, was significantly higher in old compared to young normal subjects (0.33 vs. 0.02%, p < 0.0001). With the exception of a single polymyositis biopsy specimen showing a large number of ragged red fibers, the frequency of ragged red fibers in patients with polymyositis or dermatomyositis was similar to that of age-matched normal control subjects. The frequency of ragged red fibers was more than 1% in 7 of 8 patients with inclusion body myositis (maximum, 15%). The modified succinic dehydrogenase stain was more sensitive than the modified Gomori trichrome in detecting accumulation of mitochondria in muscle fibers. Cytochrome c oxidase activity was deficient in most ragged red fibers. We conclude that the number of ragged red fibers increases with normal aging and may reflect an age-related decline in muscle mitochondrial oxidative metabolism. The frequent occurrence of ragged red fibers in inclusion body myositis suggests that mitochondrial function may be impaired in this disease.

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Aging-associated Deletions of Human Diaphragmatic Mitochondrial DNA

Cited by 46 publications

References 18 publications

Diaphragm abnormalities in heart failure and aging: mechanisms and integration of cardiovascular and respiratory pathophysiology

Diaphragm abnormalities in heart failure and aging: mechanisms and integration of cardiovascular and respiratory pathophysiology

Mitochondrial DNA deletion and sarcopenia

Ragged Red Fibers in Normal Aging and Inflammatory Myopathy

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