Indoxyl sulfate mediates low handgrip strength and is predictive of high hospitalization rates in patients with end-stage renal disease

Hou, Yi‐Chou; Liu, Yueh-Min; Liao, Min-Ter; Zheng, Cai Mei; Lu, Cheng Wei; Liu, Wen-Chih; Hung, Kuo-Chin; Lin, Shyh-Min; Lu, Kuo‐Cheng

doi:10.3389/fmed.2023.1023383

Cited by 5 publications

(4 citation statements)

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“…The in vivo study demonstrated the similar number of nuclei in the skeletal muscle, and the myoD expression was similar after IS treatment in the in vitro study. The clinical data demonstrated that the skeletal muscle mass did not have the association with the concentration of indoxyl sulfate [ 24 ]. Therefore, the IS might not influence the skeletal muscle viability or the direct destruction on the myotube.…”

Section: Discussionmentioning

confidence: 99%

Indoxyl sulfate induced frailty in patients with end-stage renal disease by disrupting the PGC-1α–FNDC5 axis

Hou,

Liao,

Tsai

et al. 2023

Aging

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Objective: Sarcopenia or frailty is common among patients with chronic kidney disease (CKD). The protein-bound uremic toxin indoxyl sulfate (IS) is associated with frailty. IS induces apoptosis and disruption of mitochondrial activity in skeletal muscle. However, the association of IS with anabolic myokines such as irisin in patients with CKD or end-stage renal disease (ESRD) is unclear. This study aims to elucidate whether IS induces frailty by dysregulating irisin in patients with CKD. Materials and Methods: The handgrip strength of 53 patients, including 28 patients with ESRD, was examined. Serum concentrations of IS and irisin were analyzed. CKD was established in BALB/c mice through 5/6 nephrectomy. Pathologic analysis of skeletal muscle was assessed through haematoxylin and eosin and Masson’s trichrome staining. Expression of peroxisome proliferator-activated receptor-gamma coactivator PGC-1α and irisin were analyzed using real-time polymerase chain reaction and Western blotting. Results: Handgrip strength was lower among patients with ESRD than among those without ESRD. In total, 64.3% and 24% of the patients in the ESRD and control groups had low handgrip strength, respectively ( p < 0.05). Serum concentrations of IS were significantly higher in the ESRD group than in the control group (222.81 ± 90.67 μM and 23.19 ± 33.28 μM, respectively, p < 0.05). Concentrations of irisin were lower in the ESRD group than in the control group (64.62 ± 32.64 pg/mL vs. 99.77 ± 93.29 pg/mL, respectively, p < 0.05). ROC curves for low handgrip strength by irisin and IS were 0.298 (95% confidence interval (CI): 0.139–0.457, p < 0.05) and 0.733 (95% CI: 0.575–0.890, p < 0.05), respectively. The percentage of collagen was significantly higher in mice with 5/6 nephrectomy than in the control group. After resveratrol (RSV) treatment, the percentage of collagen significantly decreased. RSV modulates TGF-β signaling. In vitro analysis revealed that IS treatment suppressed expression of PGC-1α and FNDC5 in a dose–dependent manner, whereas RSV treatment attenuated IS-induced phenomena in C2C12 cells. Conclusion: IS was positively correlated with frailty in patients with ESRD through the modulation of the PGC-1α–FNDC5 axis. RSV may be a potential drug for reversing IS-induced suppression of the PGC-1α–FNDC5 axis in skeletal muscle.

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Section: Discussionmentioning

confidence: 99%

Indoxyl sulfate induced frailty in patients with end-stage renal disease by disrupting the PGC-1α–FNDC5 axis

Hou,

Liao,

Tsai

et al. 2023

Aging

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“…Our recent clinical cohort found that ESRD patients had low handgrip strength, possibly due to higher levels of IS [143]. Elevated IS levels are associated with muscle issues, and incorporating AST-120 in CKD treatment shows promise for improving sarcopenia [144].…”

Section: Crosslinks Between Bones and Musclesmentioning

confidence: 98%

The Potential Influence of Uremic Toxins on the Homeostasis of Bones and Muscles in Chronic Kidney Disease

et al. 2023

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Patients with chronic kidney disease (CKD) often experience a high accumulation of protein-bound uremic toxins (PBUTs), specifically indoxyl sulfate (IS) and p-cresyl sulfate (pCS). In the early stages of CKD, the buildup of PBUTs inhibits bone and muscle function. As CKD progresses, elevated PBUT levels further hinder bone turnover and exacerbate muscle wasting. In the late stage of CKD, hyperparathyroidism worsens PBUT-induced muscle damage but can improve low bone turnover. PBUTs play a significant role in reducing both the quantity and quality of bone by affecting osteoblast and osteoclast lineage. IS, in particular, interferes with osteoblastogenesis by activating aryl hydrocarbon receptor (AhR) signaling, which reduces the expression of Runx2 and impedes osteoblast differentiation. High PBUT levels can also reduce calcitriol production, increase the expression of Wnt antagonists (SOST, DKK1), and decrease klotho expression, all of which contribute to low bone turnover disorders. Furthermore, PBUT accumulation leads to continuous muscle protein breakdown through the excessive production of reactive oxygen species (ROS) and inflammatory cytokines. Interactions between muscles and bones, mediated by various factors released from individual tissues, play a crucial role in the mutual modulation of bone and muscle in CKD. Exercise and nutritional therapy have the potential to yield favorable outcomes. Understanding the underlying mechanisms of bone and muscle loss in CKD can aid in developing new therapies for musculoskeletal diseases, particularly those related to bone loss and muscle wasting.

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“…Indoxyl sulfate, which is derived from the breakdown of tryptophan, is the most studied uremic toxin in regard to pathologic actions on tissues. The elevated serum levels of indoxyl sulfate are associated with reduced muscle strength in ESRD patients [217]. Experimental studies have shown that indoxyl sulfate induces morphological changes in mitochondria, impairs mitochondrial function, and stimulates excessive ROS production and myostatin expression, resulting in myofiber atrophy [85,[218][219][220].…”

Section: Mechanisms Of Ckd-associated Sarcopeniamentioning

confidence: 99%

Skeletal Muscle Injury in Chronic Kidney Disease—From Histologic Changes to Molecular Mechanisms and to Novel Therapies

Heitman,

Alexander,

Faul

2024

IJMS

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Chronic kidney disease (CKD) is associated with significant reductions in lean body mass and in the mass of various tissues, including skeletal muscle, which causes fatigue and contributes to high mortality rates. In CKD, the cellular protein turnover is imbalanced, with protein degradation outweighing protein synthesis, leading to a loss of protein and cell mass, which impairs tissue function. As CKD itself, skeletal muscle wasting, or sarcopenia, can have various origins and causes, and both CKD and sarcopenia share common risk factors, such as diabetes, obesity, and age. While these pathologies together with reduced physical performance and malnutrition contribute to muscle loss, they cannot explain all features of CKD-associated sarcopenia. Metabolic acidosis, systemic inflammation, insulin resistance and the accumulation of uremic toxins have been identified as additional factors that occur in CKD and that can contribute to sarcopenia. Here, we discuss the elevation of systemic phosphate levels, also called hyperphosphatemia, and the imbalance in the endocrine regulators of phosphate metabolism as another CKD-associated pathology that can directly and indirectly harm skeletal muscle tissue. To identify causes, affected cell types, and the mechanisms of sarcopenia and thereby novel targets for therapeutic interventions, it is important to first characterize the precise pathologic changes on molecular, cellular, and histologic levels, and to do so in CKD patients as well as in animal models of CKD, which we describe here in detail. We also discuss the currently known pathomechanisms and therapeutic approaches of CKD-associated sarcopenia, as well as the effects of hyperphosphatemia and the novel drug targets it could provide to protect skeletal muscle in CKD.

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Indoxyl sulfate mediates low handgrip strength and is predictive of high hospitalization rates in patients with end-stage renal disease

Cited by 5 publications

References 92 publications

Indoxyl sulfate induced frailty in patients with end-stage renal disease by disrupting the PGC-1α–FNDC5 axis

Indoxyl sulfate induced frailty in patients with end-stage renal disease by disrupting the PGC-1α–FNDC5 axis

The Potential Influence of Uremic Toxins on the Homeostasis of Bones and Muscles in Chronic Kidney Disease

Skeletal Muscle Injury in Chronic Kidney Disease—From Histologic Changes to Molecular Mechanisms and to Novel Therapies

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