3 results found
farre garros, paul R, connolly M, et al., 2017, miR-542 promotes mitochondrial dysfunction and SMAD activity and is raised in ICU Acquired Weakness, American Journal of Respiratory and Critical Care Medicine, Vol: 196, Pages: 1-12, ISSN: 1073-449X
Rationale: Loss of skeletal muscle mass and function is a common consequence of critical illness and a range of chronic diseases but the mechanisms by which this occurs are unclear. Objectives: We aimed to identify miRNAs that were increased in the quadriceps of patients with muscle wasting and to determine the molecular pathways by which they contributed to muscle dysfunction. Methods: miR-542-3p/-5p were quantified in the quadriceps of patients with COPD and intensive care unit acquired weakness (ICUAW). The effect of miR-542-3p/5p was determined on mitochondrial function and TGF-β signaling in vitro and in vivo. Measurements and main results: miR-542-3p/5p were elevated in patients with COPD but more markedly in patients with ICUAW. In vitro, miR-542-3p suppressed the expression of the mitochondrial ribosomal protein MRPS10, and reduced 12S rRNA expression suggesting mitochondrial ribosomal stress. miR-542-5p increased nuclear phospho-SMAD2/3 and suppressed expression of SMAD7, SMURF1 and PPP2CA, proteins that inhibit or reduce SMAD2/3 phosphorylation suggesting that miR-542-5p increased TGF-β signaling. In mice, miR-542 over-expression caused muscle wasting, reduced mitochondrial function, 12S rRNA expression and SMAD7 expression, consistent with the effects of the miRNAs in vitro. Similarly, in patients with ICUAW, the expression of 12S rRNA and of the inhibitors of SMAD2/3 phosphorylation were reduced, indicative of mitochondrial ribosomal stress and increased TGF-β signaling. In patients undergoing aortic surgery, pre-operative levels of miR-542-3p/5p were positively correlated with muscle loss following surgery. Conclusion; Elevated miR-542-3p/5p may cause muscle atrophy in ICU patients through the promotion of mitochondrial dysfunction and activation of SMAD2/3 phosphorylation.
Patel MS, Lee J, Baz M, et al., 2015, Growth differentiation factor-15 is associated with muscle mass in chronic obstructive pulmonary disease and promotes muscle wasting in vivo, Journal of Cachexia, Sarcopenia and Muscle, Vol: 7, Pages: 436-448, ISSN: 2190-6009
BackgroundLoss of muscle mass is a co-morbidity common to a range of chronic diseases including chronic obstructive pulmonary disease (COPD). Several systemic features of COPD including increased inflammatory signalling, oxidative stress, and hypoxia are known to increase the expression of growth differentiation factor-15 (GDF-15), a protein associated with muscle wasting in other diseases. We therefore hypothesized that GDF-15 may contribute to muscle wasting in COPD.MethodsWe determined the expression of GDF-15 in the serum and muscle of patients with COPD and analysed the association of GDF-15 expression with muscle mass and exercise performance. To determine whether GDF-15 had a direct effect on muscle, we also determined the effect of increased GDF-15 expression on the tibialis anterior of mice by electroporation.ResultsGrowth differentiation factor-15 was increased in the circulation and muscle of COPD patients compared with controls. Circulating GDF-15 was inversely correlated with rectus femoris cross-sectional area (P < 0.001) and exercise capacity (P < 0.001) in two separate cohorts of patients but was not associated with body mass index. GDF-15 levels were associated with 8-oxo-dG in the circulation of patients consistent with a role for oxidative stress in the production of this protein. Local over-expression of GDF-15 in mice caused wasting of the tibialis anterior muscle that expressed it but not in the contralateral muscle suggesting a direct effect of GDF-15 on muscle mass (P < 0.001).ConclusionsTogether, the data suggest that GDF-15 contributes to the loss of muscle mass in COPD.
Price LC, Shao D, Meng C, et al., 2015, Dexamethasone induces apoptosis in pulmonary arterial smooth musclecells, Respiratory Research, Vol: 16, ISSN: 1465-993X
BackgroundDexamethasone suppressed inflammation and haemodynamic changes inan animal model of pulmonary arterial hypertension (PAH). A majortarget for dexamethasone actions is NFκB, which is activated inpulmonary vascular cells and perivascular inflammatory cells in PAH.Reverse remodelling is an important concept in PAH disease therapy,and further to its antiproliferative effects, we sought to explore whetherdexamethasone augments pulmonary arterial smooth muscle cell(PASMC) apoptosis.MethodsAnalysis of apoptosis markers (caspase 3, insitu DNA fragmentation)and NFκB (p65 and phosphoIKKα/β) activation was performed onlung tissue from rats with monocrotaline (MCT)induced pulmonaryhypertension (PH), before and after day 14–28 treatment withdexamethasone (5 mg/kg/day). PASMC were cultured from this rat PHmodel and from normal human lung following lung cancer surgery.Following stimulation with TNFα (10 ng/ml), the effects ofdexamethasone (10 –10 M) and IKK2 (NFκB) inhibition12345−8 −6−626/08/2015 e.Proofinghttp://eproofing.springer.com/journals/printpage.php?token=z1f6oNo2TW2b02e3UtS87S7AQ0qS0Cpd07hxhERYg8 3/38(AS602868, 0–3 μM (03×10 M) on IL6 and CXCL8 release andapoptosis was determined by ELISA and by Hoechst staining. NFκBactivation was measured by TransAm assay.ResultsDexamethasone treatment of rats with MCTinduced PH in vivo led toPASMC apoptosis as displayed by increased caspase 3 expression andDNA fragmentation. A similar effect was seen in vitro using TNFαsimulated human and rat PASMC following both dexamethasone andIKK2 inhibition. Increased apoptosis was associated with a reduction inNFκB activation and in IL6 and CXCL8 release from PASMC.ConclusionsDexamethasone exerted reverseremodelling effects by augmentingapoptosis and reversing inflammation in PASMC possibly via i
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