Journal
PHYSIOLOGICAL REPORTS
Volume 4, Issue 9, Pages -Publisher
WILEY-BLACKWELL
DOI: 10.14814/phy2.12780
Keywords
BNIP3; chronic kidney disease; mitochondria; mitochondrial DNA copy number; oxidative stress; PGC1 alpha; skeletal muscle
Categories
Funding
- NCRR NIH HHS [1UL-1RR024975, UL1 RR024975] Funding Source: Medline
- NHLBI NIH HHS [R01 HL065193, 5R01HL065193] Funding Source: Medline
- NIAMS NIH HHS [F32AR061946, F32 AR061946] Funding Source: Medline
- NIDDK NIH HHS [DK020593, K24DK062849, K23DK100533, K23 DK099442, K23 DK100533, K24 DK062849] Funding Source: Medline
- NIGMS NIH HHS [K23GM102676, T32GM07569, K23 GM102676, R01 GM112871, R01GM112871] Funding Source: Medline
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Mitochondria abnormalities in skeletal muscle may contribute to frailty and sarcopenia, commonly present in patients with chronic kidney disease (CKD). Dysfunctional mitochondria are also a major source of oxidative stress and may contribute to cardiovascular disease in CKD. We tested the hypothesis that mitochondrial structure and function worsens with the severity of CKD. Mitochondrial volume density, mitochondrial DNA (mtDNA) copy number, BNIP3, and PGC1 alpha protein expression were evaluated in skeletal muscle biopsies obtained from 27 subjects (17 controls and 10 with CKD stage 5 on hemodialysis). We also measured mtDNA copy number in peripheral blood mononuclear cells (PBMCs), plasma isofurans, and plasma F2-isoprostanes in 208 subjects divided into three groups: non-CKD (eGFR>60 mL/min), CKD stage 3-4 (eGFR 60-15 mL/min), and CKD stage 5 (on hemodialysis). Muscle biopsies from patients with CKD stage 5 revealed lower mitochondrial volume density, lower mtDNA copy number, and higher BNIP3 content than controls. mtDNA copy number in PBMCs was decreased with increasing severity of CKD: non-CKD (6.48, 95% CI 4.49-8.46), CKD stage 3-4 (3.30, 95% CI 0.85-5.75, P = 0.048 vs. non-CKD), and CKD stage 5 (1.93, 95% CI 0.27-3.59, P = 0.001 vs. non-CKD). Isofurans were higher in patients with CKD stage 5 (median 59.21 pg/mL, IQR 41.76-95.36) compared to patients with non-CKD (median 49.95 pg/mL, IQR 27.88-83.46, P = 0.001), whereas F2-isoprostanes did not differ among groups. Severity of CKD is associated with mitochondrial dysfunction and markers of oxidative stress. Mitochondrial abnormalities, which are common in skeletal muscle from patients with CKD stage 5, may explain the muscle dysfunction associated with frailty and sarcopenia in CKD. Further studies are required to evaluate mitochondrial function in vivo in patients with different CKD stages.
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