Skeletal Muscle Mitochondrial Dysfunction Is Present in Patients with CKD before Initiation of Maintenance Hemodialysis

Background and objectivesPatients with CKD suffer from frailty and sarcopenia, which is associated with higher morbidity and mortality. Skeletal muscle mitochondria are important for physical function and could be a target to prevent frailty and sarcopenia. In this study, we tested the hypothesis that mitochondrial dysfunction is associated with the severity of CKD. We also evaluated the interaction between mitochondrial function and coexisting comorbidities, such as impaired physical performance, intermuscular adipose tissue infiltration, inflammation, and oxidative stress.Design, setting, participants, & measurements Sixty-three participants were studied, including controls (n=21), patients with CKD not on maintenance hemodialysis (CKD 3–5; n=20), and patients on maintenance hemodialysis (n=22). We evaluated in vivo knee extensors mitochondrial function using 31P magnetic resonance spectroscopy to obtain the phosphocreatine recovery time constant, a measure of mitochondrial function. We measured physical performance using the 6-minute walk test, intermuscular adipose tissue infiltration with magnetic resonance imaging, and markers of inflammation and oxidative stress in plasma. In skeletal muscle biopsies from a select number of patients on maintenance hemodialysis, we also measured markers of mitochondrial dynamics (fusion and fission).ResultsWe found a prolonged phosphocreatine recovery constant in patients on maintenance hemodialysis (53.3 [43.4–70.1] seconds, median [interquartile range]) and patients with CKD not on maintenance hemodialysis (41.5 [35.4–49.1] seconds) compared with controls (38.9 [32.5–46.0] seconds; P=0.001 among groups). Mitochondrial dysfunction was associated with poor physical performance (r=0.62; P=0.001), greater intermuscular adipose tissue (r=0.44; P=0.001), and increased markers of inflammation and oxidative stress (r=0.60; P=0.001). We found mitochondrial fragmentation and increased content of dynamin-related protein 1, a marker of mitochondrial fission, in skeletal muscles from patients on maintenance hemodialysis (0.86 [0.48–1.35] arbitrary units (A.U.), median [interquartile range]) compared with controls (0.60 [0.24–0.75] A.U.).ConclusionsMitochondrial dysfunction is due to multifactorial etiologies and presents prior to the initiation of maintenance hemodialysis, including in patients with CKD stages 3–5.

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MO045MITOCHONDRIAL DYSFUNCTION AND MUSCLE ENERGETICS IN CKD PATIENTS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa140.mo045 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Jorge Gamboa ◽

Alp Ikizler ◽

Chang Yu ◽

Bruce Damon ◽

Nancy Brown ◽

...

Keyword(s):

Oxidative Stress ◽

Mitochondrial Dysfunction ◽

Physical Function ◽

Physical Performance ◽

Mitochondrial Function ◽

Resonance Spectroscopy ◽

Muscle Energetics ◽

Intermuscular Adipose Tissue ◽

Markers Of Inflammation ◽

And Oxidative Stress

Abstract Background and Aims Patients with chronic kidney disease (CKD) suffer from frailty and sarcopenia. Skeletal muscle mitochondria are important for physical function and could be a target to prevent frailty and sarcopenia. Method We tested the hypothesis that mitochondrial function worsens with the progression of CKD. We evaluated the interaction between mitochondrial function and co-existing comorbidities such as impaired physical performance, intermuscular adipose tissue (IMAT) infiltration, inflammation, and oxidative stress. We evaluated in-vivo thigh mitochondrial function using 31-phosphorus magnetic resonance spectroscopy to obtain the phosphocreatine (PCr) recovery constant, a measure of mitochondrial function. We measured physical performance using the six-minute walk test, IMAT infiltration and markers of inflammation in plasma. Results Sixty-three participants were studied including controls (n=21), patients with CKD not on maintenance hemodialysis (MHD; n=20), and patients on MHD (n=22). We found a prolonged PCr recovery constant in patients on MHD (53.3 (43.4, 70.1) seconds) and with CKD not on MHD (46.3 (40,0, 49.9) seconds) compared to controls (34.2 (28.8, 43.7) seconds) (p<0.001 between groups), Figure 1A-C. Mitochondrial dysfunction was associated with poor physical performance, greater IMAT, and increased markers of inflammation Figure 2A-C. Conclusion Mitochondrial function worsens with the progression of CKD and correlates with physical function, IMAT, inflammation, and oxidative stress. These data suggest that therapeutic approaches targeted at mitochondrial dysfunction and dynamics could prevent or treat frailty and sarcopenia in patients CKD.

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Visceral and Subcutaneous Adipose Tissue Volumes Are Cross-Sectionally Related to Markers of Inflammation and Oxidative Stress

Circulation ◽

10.1161/circulationaha.107.710509 ◽

2007 ◽

Vol 116 (11) ◽

pp. 1234-1241 ◽

Cited By ~ 548

Author(s):

Karla M. Pou ◽

Joseph M. Massaro ◽

Udo Hoffmann ◽

Ramachandran S. Vasan ◽

Pal Maurovich-Horvat ◽

...

Keyword(s):

Oxidative Stress ◽

Adipose Tissue ◽

Subcutaneous Adipose Tissue ◽

Markers Of Inflammation ◽

Subcutaneous Adipose ◽

And Oxidative Stress

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Effect of eccentric training on mitochondrial function and oxidative stress in the skeletal muscle of rats

Brazilian Journal of Medical and Biological Research ◽

10.1590/1414-431x20121956 ◽

2013 ◽

Vol 46 (1) ◽

pp. 14-20 ◽

Cited By ~ 9

Author(s):

L.A. Silva ◽

K.F. Bom ◽

C.B. Tromm ◽

G.L. Rosa ◽

I. Mariano ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Mitochondrial Function ◽

Eccentric Training ◽

And Oxidative Stress

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Centella asiatica Attenuates Mitochondrial Dysfunction and Oxidative Stress in Aβ-Exposed Hippocampal Neurons

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/7023091 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 12

Author(s):

Nora E. Gray ◽

Jonathan A. Zweig ◽

Donald G. Matthews ◽

Maya Caruso ◽

Joseph F. Quinn ◽

...

Keyword(s):

Oxidative Stress ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Hippocampal Neurons ◽

Neuroblastoma Cells ◽

Water Extract ◽

Centella Asiatica ◽

Antioxidant Response ◽

And Oxidative Stress

Centella asiatica has been used for centuries to enhance memory. We have previously shown that a water extract of Centella asiatica (CAW) protects against the deleterious effects of amyloid-β (Aβ) in neuroblastoma cells and attenuates Aβ-induced cognitive deficits in mice. Yet, the neuroprotective mechanism of CAW has yet to be thoroughly explored in neurons from these animals. This study investigates the effects of CAW on neuronal metabolism and oxidative stress in isolated Aβ-expressing neurons. Hippocampal neurons from amyloid precursor protein overexpressing Tg2576 mice and wild-type (WT) littermates were treated with CAW. In both genotypes, CAW increased the expression of antioxidant response genes which attenuated the Aβ-induced elevations in reactive oxygen species (ROS) and lipid peroxidation in Tg2576 neurons. CAW also improved mitochondrial function in both genotypes and increased the expression of electron transport chain enzymes and mitochondrial labeling, suggesting an increase in mitochondrial content. These data show that CAW protects against mitochondrial dysfunction and oxidative stress in Aβ-exposed hippocampal neurons which could contribute to the beneficial effects of the extract observed in vivo. Since CAW also improved mitochondrial function in the absence of Aβ, these results suggest a broader utility for other conditions where neuronal mitochondrial dysfunction occurs.

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Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.617588 ◽

2021 ◽

Vol 13 ◽

Cited By ~ 1

Author(s):

Afzal Misrani ◽

Sidra Tabassum ◽

Li Yang

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Mitochondrial Dynamics ◽

Mitochondrial Morphology ◽

Therapeutic Approaches ◽

The Impact ◽

And Oxidative Stress

Mitochondria play a pivotal role in bioenergetics and respiratory functions, which are essential for the numerous biochemical processes underpinning cell viability. Mitochondrial morphology changes rapidly in response to external insults and changes in metabolic status via fission and fusion processes (so-called mitochondrial dynamics) that maintain mitochondrial quality and homeostasis. Damaged mitochondria are removed by a process known as mitophagy, which involves their degradation by a specific autophagosomal pathway. Over the last few years, remarkable efforts have been made to investigate the impact on the pathogenesis of Alzheimer’s disease (AD) of various forms of mitochondrial dysfunction, such as excessive reactive oxygen species (ROS) production, mitochondrial Ca2+ dyshomeostasis, loss of ATP, and defects in mitochondrial dynamics and transport, and mitophagy. Recent research suggests that restoration of mitochondrial function by physical exercise, an antioxidant diet, or therapeutic approaches can delay the onset and slow the progression of AD. In this review, we focus on recent progress that highlights the crucial role of alterations in mitochondrial function and oxidative stress in the pathogenesis of AD, emphasizing a framework of existing and potential therapeutic approaches.

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Skeletal Muscle Mitochondrial Dysfunction and Oxidative Stress in Peripheral Arterial Disease: A Unifying Mechanism and Therapeutic Target

Antioxidants ◽

10.3390/antiox9121304 ◽

2020 ◽

Vol 9 (12) ◽

pp. 1304

Author(s):

Kyoungrae Kim ◽

Erik M. Anderson ◽

Salvatore T. Scali ◽

Terence E. Ryan

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Blood Flow ◽

Mitochondrial Dysfunction ◽

Strong Predictor ◽

Clinical Pathology ◽

Arterial Disease ◽

Limb Amputation ◽

Peripheral Arterial ◽

And Oxidative Stress

Peripheral artery disease (PAD) is caused by atherosclerosis in the lower extremities, which leads to a spectrum of life-altering symptomatology, including claudication, ischemic rest pain, and gangrene requiring limb amputation. Current treatments for PAD are focused primarily on re-establishing blood flow to the ischemic tissue, implying that blood flow is the decisive factor that determines whether or not the tissue survives. Unfortunately, failure rates of endovascular and revascularization procedures remain unacceptably high and numerous cell- and gene-based vascular therapies have failed to demonstrate efficacy in clinical trials. The low success of vascular-focused therapies implies that non-vascular tissues, such as skeletal muscle and oxidative stress, may substantially contribute to PAD pathobiology. Clues toward the importance of skeletal muscle in PAD pathobiology stem from clinical observations that muscle function is a strong predictor of mortality. Mitochondrial impairments in muscle have been documented in PAD patients, although its potential role in clinical pathology is incompletely understood. In this review, we discuss the underlying mechanisms causing mitochondrial dysfunction in ischemic skeletal muscle, including causal evidence in rodent studies, and highlight emerging mitochondrial-targeted therapies that have potential to improve PAD outcomes. Particularly, we will analyze literature data on reactive oxygen species production and potential counteracting endogenous and exogenous antioxidants.

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