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Toll-like receptor 4 signalling mediates inflammation in skeletal muscle of
patients with chronic kidney disease
#MMPMID27897392
Verzola D
; Bonanni A
; Sofia A
; Montecucco F
; D'Amato E
; Cademartori V
; Parodi EL
; Viazzi F
; Venturelli C
; Brunori G
; Garibotto G
J Cachexia Sarcopenia Muscle
2017[Feb]; 8
(1
): 131-144
PMID27897392
show ga
BACKGROUND: Inflammation in skeletal muscle is implicated in the pathogenesis of
insulin resistance and cachexia but why uremia up-regulates pro-inflammatory
cytokines is unknown. Toll-like receptors (TLRs) regulate locally the innate
immune responses, but it is unknown whether in chronic kidney disease (CKD) TLR4
muscle signalling is altered. The aim of the study is to investigate whether in
CKD muscle, TLRs had abnormal function and may be involved in transcription of
pro-inflammatory cytokine. METHODS: TLR4, phospho-p65, phospho-ikB?, tumour
necrosis factor (TNF)-?, phospho p38, Murf 1, and atrogin were studied in
skeletal muscle from nondiabetic CKD stage 5 patients (n?=?29) and controls
(n?=?14) by immunohistochemistry, western blot, and RT-PCR. Muscle cell cultures
(C2C12) exposed to uremic serum were employed to study TLR4 expression (western
blot and RT-PCR) and TLR-driven signalling. TLR4 signalling was abrogated by a
small molecule chemical inhibitor or TLR4 siRNA. Phospho AKT and phospho p38 were
evaluated by western blot. RESULTS: CKD subjects had elevated TLR4 gene and
protein expression. Also expression of NFkB, p38 MAPK and the NFkB-regulated gene
TNF-? was increased. At multivariate analysis, TLR4 protein content was predicted
by eGFR and Subjective Global Assessment, suggesting that the progressive decline
in renal function and wasting mediate TLR4 activation. In C2C12, uremic serum
increased TLR4 as well as TNF-? and down-regulated pAkt. These effects were
prevented by blockade of TLR4. CONCLUSIONS: CKD promotes muscle inflammation
through an up-regulation of TLR4, which may activate downward inflammatory
signals such as TNF-? and NFkB-regulated genes.
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