Ventilator‐induced diaphragmatic dysfunction in <i>MDX</i> mice

Liang, Feng; Li, Tong; Azuelos, Ilan; Giordano, Christian; Liang, Han; Hussain, Sabah N. A.; Matecki, Stéfan; Petrof, Basil J.

doi:10.1002/mus.25760

Cited by 13 publications

(14 citation statements)

References 41 publications

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“…Protein was extracted from frozen diaphragm samples, and antibody dilutions were selected according to the manufacturers’ instructions. The following proteins were analyzed as previously described: (1) total and phosphorylated (Tyr705) forms of STAT3 (clones 124H6 and D3A7, Cell Signaling, USA); (2) carbonylated proteins (Oxyblot Protein Oxidation Detection Kit, Millipore, Germany) and 4-hydroxynonenal (4-HNE; R&D Systems, USA) as indices of oxidative stress; and (3) LC3B-I and LC3B-II levels (clone D11, Cell Signaling, USA) as indices of autophagy [8, 18, 19]. Immunoreactive bands were visualized using enhanced chemiluminescence and Ponceau red for protein loading.…”

Section: Methodsmentioning

confidence: 99%

“…Primer sequences for genes involved in STAT3 activation (IL-6), the ubiquitin-proteasome pathway of proteolysis (Atrogin1, MuRF1), metabolism (SIRT1), autophagy (LC3B, Gabarapl1), and myosin heavy chain (MyHC) isoforms (1, 2a, 2x, embryonic, neonatal) are shown in Additional file 1: Table S1. The data are expressed as n -fold change relative to the average CTL group value according to the standard ΔΔ CT method [8, 18, 19].…”

Section: Methodsmentioning

confidence: 99%

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Mechanical ventilation causes diaphragm dysfunction in newborn lambs

et al. 2019

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Background Diaphragm weakness occurs rapidly in adult animals treated with mechanical ventilation (MV), but the effects of MV on the neonatal diaphragm have not been determined. Furthermore, it is unknown whether co-existent lung disease exacerbates ventilator-induced diaphragmatic dysfunction (VIDD). We investigated the impact of MV (mean duration = 7.65 h), either with or without co-existent respiratory failure caused by surfactant deficiency, on the development of VIDD in newborn lambs. Methods Newborn lambs (1–4 days) were assigned to control (CTL, non-ventilated), mechanically ventilated (MV), and MV + experimentally induced surfactant deficiency (MV+SD) groups. Immunoblotting and quantitative PCR assessed inflammatory signaling, the ubiquitin-proteasome system, autophagy, and oxidative stress. Immunostaining for myosin heavy chain (MyHC) isoforms and quantitative morphometry evaluated diaphragm atrophy. Contractile function of the diaphragm was determined in isolated myofibrils ex vivo. Results Equal decreases (25–30%) in myofibrillar force generation were found in MV and MV+SD diaphragms compared to CTL. In comparison to CTL, both MV and MV+SD diaphragms also demonstrated increased STAT3 transcription factor phosphorylation. Ubiquitin-proteasome system (Atrogin1 and MuRF1) transcripts and autophagy indices (Gabarapl1 transcripts and the ratio of LC3B-II/LC3B-I protein) were greater in MV+SD relative to MV alone, but fiber type atrophy was not observed in any group. Protein carbonylation and 4-hydroxynonenal levels (indices of oxidative stress) also did not differ among groups. Conclusions In newborn lambs undergoing controlled MV, there is a rapid onset of diaphragm dysfunction consistent with VIDD. Superimposed lung injury caused by surfactant deficiency did not influence the severity of early diaphragm weakness. Electronic supplementary material The online version of this article (10.1186/s13054-019-2409-6) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Mechanical ventilation causes diaphragm dysfunction in newborn lambs

et al. 2019

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“…Once activated, pSTAT3 dimerizes and enters the nucleus to activate transcription of various genes (Figure 1). STAT3 signaling has been shown to be activated in skeletal muscle and promotes skeletal muscle atrophy in muscle diseases, such as Duchenne muscular dystrophy (DMD), and Merosin-deficient congenital muscular dystrophy (MDC1A), as well as cancer and sepsis [7,8,9]. In addition to skeletal muscles, STAT3 signaling has been shown to play critical roles in both vascular and central nervous systems, thus directly and indirectly contributing to muscle health [10,11,12,13].…”

Section: Introductionmentioning

confidence: 99%

STAT3 in Skeletal Muscle Function and Disorders

Guadagnin

Mázala

Chen

2018

IJMS

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Signal transducer and activator of transcription 3 (STAT3) signaling plays critical roles in regulating skeletal muscle mass, repair, and diseases. In this review, we discuss the upstream activators of STAT3 in skeletal muscles, with a focus on interleukin 6 (IL6) and transforming growth factor beta 1 (TGF-β1). We will also discuss the double-edged effect of STAT3 activation in the muscles, including the role of STAT3 signaling in muscle hypertrophy induced by exercise training or muscle wasting in cachectic diseases and muscular dystrophies. STAT3 is a critical regulator of satellite cell self-renewal after muscle injury. STAT3 knock out affects satellite cell myogenic progression by impairing proliferation and inducing premature differentiation. Recent studies in STAT3 signaling demonstrated its direct role in controlling myogenic capacity of myoblasts and satellite cells, as well as the potential benefit in using STAT3 inhibitors to treat muscle diseases. However, prolonged STAT3 activation in muscles has been shown to be responsible for muscle wasting by activating protein degradation pathways. It is important to balance the extent of STAT3 activation and the duration and location (cell types) of the STAT3 signaling when developing therapeutic interventions. STAT3 signaling in other tissues and organs that can directly or indirectly affects skeletal muscle health are also discussed.

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“…When DMD is coupled with MV for respiratory support, a more progressive pathology could theoretically ensue. In this issue of the journal, Liang and colleagues investigate the impact of MV in the context of an underlying neuromuscular disease, where the widely used dystrophic mouse model ( mdx ) was subjected to a brief 6‐hour period of MV . The authors hypothesized the previously reported features associated with VIDD (i.e., oxidative stress, upregulation of proteolytic and catabolic skeletal muscle pathways, and muscle weakness) were also present in the mdx mouse diaphragm after MV.…”

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confidence: 99%

“…In their work, the Liang et al . also identify the experimental MV duration as clinically analogous to nocturnal ventilation . Nocturnal noninvasive ventilation (NIV) is indicated in DMD patients with evidence of sleep‐disordered breathing or hypoventilation, and, in conjunction with airway clearance assistance and lung volume recruitment therapy, it forms the cornerstone of current respiratory management of DMD .…”

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confidence: 99%