Reduced skeletal muscle expression of mitochondrial-derived peptides humanin and MOTS-C and Nrf2 in chronic kidney disease

Advanced chronic kidney disease (CKD) is characterized by a premature aging phenotype of multifactorial origin. Mitochondrial dysfunction is prevalent in CKD and has been proposed as a major contributor to poor muscle function. Although the mitochondria-derived peptides (MDPs) humanin and mitochondrial open reading frame of 12S rRNA-c (MOTS-c) are involved in cell survival, suppression of apoptosis, and glucose control, the implications of MDP in CKD are unknown. We investigated humanin and MOTS-c protein expression in skeletal muscle and serum levels in CKD at stage 5 (glomerular filtration rate: <15 ml/min) patients and age-matched controls with normal renal function. Whereas circulating levels of humanin were increased in CKD, local muscle expression was reduced. In contrast, MOTS-c levels were reduced in both skeletal muscle and serum in CKD. Humanin in serum correlated positively to circulating TNF levels. Reduced MDP levels in skeletal muscle were associated with lower mitochondrial density and evidence of oxidative stress. These results indicate a differential regulation of MDPs in CKD and suggest an alternative site for humanin production than skeletal muscle in the uremic milieu. MDP levels were linked to systemic inflammation and evidence of oxidative stress in the muscle, two hallmark features of premature aging and uremia.

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Skeletal Muscle Regeneration and Oxidative Stress Are Altered in Chronic Kidney Disease

PLoS ONE ◽

10.1371/journal.pone.0159411 ◽

2016 ◽

Vol 11 (8) ◽

pp. e0159411 ◽

Cited By ~ 23

Author(s):

Keith G. Avin ◽

Neal X. Chen ◽

Jason M. Organ ◽

Chad Zarse ◽

Kalisha O’Neill ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Muscle Regeneration ◽

Skeletal Muscle Regeneration ◽

And Oxidative Stress

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Atractylenolide III Attenuates Muscle Wasting in Chronic Kidney Disease via the Oxidative Stress-Mediated PI3K/AKT/mTOR Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/1875471 ◽

2019 ◽

Vol 2019 ◽

pp. 1-16 ◽

Cited By ~ 1

Author(s):

Mingqing Wang ◽

Rong Hu ◽

Yanjing Wang ◽

Lingyu Liu ◽

Haiyan You ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Skeletal Muscles ◽

Muscle Wasting ◽

Mtor Pathway ◽

C2c12 Myoblast ◽

Model Group ◽

Atractylenolide Iii

Oxidative stress contributes to muscle wasting in advanced chronic kidney disease (CKD) patients. Atractylenolide III (ATL-III), the major active constituent of Atractylodes rhizome, has been previously reported to function as an antioxidant. This study is aimed at investigating whether ATL-III has protective effects against CKD-induced muscle wasting by alleviating oxidative stress. The results showed that the levels of serum creatinine (SCr), blood urea nitrogen (BUN), and urinary protein significantly decreased in the ATL-III treatment group compared with the 5/6 nephrectomy (5/6 Nx) model group but were higher than those in the sham operation group. Skeletal muscle weight was increased, while inflammation was alleviated in the ATL-III administration group compared with the 5/6 Nx model group. ATL-III-treated rats also showed reduced dilation of the mitochondria, increased CAT, GSH-Px, and SOD activity, and decreased levels of MDA both in skeletal muscles and serum compared with 5/6 Nx model rats, suggesting that ATL-III alleviated mitochondrial damage and increased the activity of antioxidant enzymes, thus reducing the production of ROS. Furthermore, accumulated autophagosomes (APs) and autolysosomes (ALs) were reduced in the gastrocnemius (Gastroc) muscles of ATL-III-treated rats under transmission electron microscopy (TEM) together with the downregulation of LC3-II and upregulation of p62 according to Western blotting. This evidence indicated that ATL-III improved skeletal muscle atrophy and alleviated oxidative stress and autophagy in CKD rats. Furthermore, ATL-III could also increase the protein levels of p-PI3K, p-AKT, and p-mTOR in skeletal muscles in CKD rats. To further reveal the relevant mechanism, the oxidative stress-mediated PI3K/AKT/mTOR pathway was assessed, which showed that a reduced expression of p-PI3K, p-AKT, and p-mTOR in C2C12 myoblast atrophy induced by TNF-α could be upregulated by ATL-III; however, after the overexpression of Nox2 to increase ROS production, the attenuated effect was reversed. Our findings indicated that ATL-III is a potentially protective drug against muscle wasting via activation of the oxidative stress-mediated PI3K/AKT/mTOR pathway.

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Dietary Antioxidant Supplements and Uric Acid in Chronic Kidney Disease: A Review

Nutrients ◽

10.3390/nu11081911 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1911 ◽

Cited By ~ 18

Author(s):

Stefanos Roumeliotis ◽

Athanasios Roumeliotis ◽

Evangelia Dounousi ◽

Theodoros Eleftheriadis ◽

Vassilios Liakopoulos

Keyword(s):

Oxidative Stress ◽

Chronic Kidney Disease ◽

Uric Acid ◽

Kidney Disease ◽

Serum Levels ◽

Maintenance Hemodialysis ◽

Antioxidant Supplements ◽

Stage Renal Disease ◽

End Stage ◽

And Oxidative Stress

Increased serum levels of uric acid have been associated with the onset and development of chronic kidney disease (CKD), cardiovascular disease, and mortality, through several molecular pathogenetic mechanisms, such as inflammation and oxidative stress. Oxidative stress is present even in the early stages of CKD, progresses parallelly with the deterioration of kidney function, and is even more exacerbated in end-stage renal disease patients undergoing maintenance hemodialysis. Although acting in the plasma as an antioxidant, once uric acid enters the intracellular environment; it behaves as a powerful pro-oxidant. Exogenous intake of antioxidants has been repeatedly shown to prevent inflammation, atherosclerosis and oxidative stress in CKD patients. Moreover, certain antioxidants have been proposed to exert uric acid-lowering properties. This review aims to present the available data regarding the effects of antioxidant supplements on both oxidative stress and uric acid serum levels, in a population particularly susceptible to oxidative damage such as CKD patients.

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AST-120 ameliorates lowered exercise capacity and mitochondrial biogenesis in the skeletal muscle from mice with chronic kidney disease via reducing oxidative stress

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfv103 ◽

2015 ◽

Vol 30 (6) ◽

pp. 934-942 ◽

Cited By ~ 40

Author(s):

Mikito Nishikawa ◽

Naoki Ishimori ◽

Shingo Takada ◽

Akimichi Saito ◽

Tomoyasu Kadoguchi ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Exercise Capacity ◽

Mitochondrial Biogenesis

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Calycosin inhibited autophagy and oxidative stress in chronic kidney disease skeletal muscle atrophy by regulating AMPK/SKP2/CARM1 signalling pathway

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.15514 ◽

2020 ◽

Vol 24 (19) ◽

pp. 11084-11099

Author(s):

Rong Hu ◽

Ming‐qing Wang ◽

Ling‐yu Liu ◽

Hai‐yan You ◽

Xiao‐hui Wu ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Muscle Atrophy ◽

Signalling Pathway ◽

Skeletal Muscle Atrophy ◽

And Oxidative Stress

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Unacylated ghrelin normalizes skeletal muscle oxidative stress and prevents muscle catabolism by enhancing tissue mitophagy in experimental chronic kidney disease

The FASEB Journal ◽

10.1096/fj.201700126r ◽

2017 ◽

Vol 31 (12) ◽

pp. 5159-5171 ◽

Cited By ~ 19

Author(s):

Gianluca Gortan Cappellari ◽

Annamaria Semolic ◽

Giulia Ruozi ◽

Pierandrea Vinci ◽

Gianfranco Guarnieri ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Unacylated Ghrelin ◽

Muscle Catabolism

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Faculty Opinions recommendation of Combined effects of ghrelin and higher food intake enhance skeletal muscle mitochondrial oxidative capacity and AKT phosphorylation in rats with chronic kidney disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1344956.816054 ◽

2009 ◽

Author(s):

Carolyn Ecelbarger

Keyword(s):

Skeletal Muscle ◽

Chronic Kidney Disease ◽

Food Intake ◽

Kidney Disease ◽

Oxidative Capacity ◽

Combined Effects ◽

Akt Phosphorylation ◽

Mitochondrial Oxidative Capacity

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Oxidative Stress in Non-Dialysis-Dependent Chronic Kidney Disease Patients

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18157806 ◽

2021 ◽

Vol 18 (15) ◽

pp. 7806

Author(s):

Patricia Tomás-Simó ◽

Luis D’Marco ◽

María Romero-Parra ◽

Mari Carmen Tormos-Muñoz ◽

Guillermo Sáez ◽

...

Keyword(s):

Oxidative Stress ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Reduced Glutathione ◽

Genetic Material ◽

Future Research ◽

Control Group ◽

Dialysis Patients ◽

Early Stages ◽

Molecular Lines

Background: Cardiovascular complications are the leading cause of morbidity and mortality at any stage of chronic kidney disease (CKD). Moreover, the high rate of cardiovascular mortality observed in these patients is associated with an accelerated atherosclerosis process that likely starts at the early stages of CKD. Thus, traditional and non-traditional or uremic-related factors represent a link between CKD and cardiovascular risk. Among non-conventional risk factors, particular focus has been placed on anaemia, mineral and bone disorders, inflammation, malnutrition and oxidative stress and, in this regard, connections have been reported between oxidative stress and cardiovascular disease in dialysis patients. Methods: We evaluated the oxidation process in different molecular lines (proteins, lipids and genetic material) in 155 non-dialysis patients at different stages of CKD and 45 healthy controls. To assess oxidative stress status, we analyzed oxidized glutathione (GSSG), reduced glutathione (GSH) and the oxidized/reduced glutathione ratio (GSSG/GSH) and other oxidation indicators, including malondialdehyde (MDA) and 8-oxo-2’-deoxyguanosine (8-oxo-dG). Results: An active grade of oxidative stress was found from the early stages of CKD onwards, which affected all of the molecular lines studied. We observed a heightened oxidative state (indicated by a higher level of oxidized molecules together with decreased levels of antioxidant molecules) as kidney function declined. Furthermore, oxidative stress-related alterations were significantly greater in CKD patients than in the control group. Conclusions: CKD patients exhibit significantly higher oxidative stress than healthy individuals, and these alterations intensify as eGFR declines, showing significant differences between CKD stages. Thus, future research is warranted to provide clearer results in this area.

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