| 1. |
- Aare, Sudhakar, et al.
(författare)
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Effects of corticosteroids in the development of limb muscle weakness in a porcine intensive care unit model
- 2013
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Ingår i: Physiological genomics. - : American Physiological Society. - 1531-2267 .- 1094-8341. ; 45:8, s. 312-320
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Tidskriftsartikel (refereegranskat)abstract
- Severe muscle wasting is a debilitating condition in critically ill intensive care unit (ICU) patients, characterized by general muscle weakness and dysfunction, resulting in a prolonged mobilization, delayed weaning from the ventilator, and a decreased quality of life post-ICU. The mechanisms underlying limb muscle weakness in ICU patients are complex and involve the impact of primary disease, but also factors common to critically ill ICU patients such as sepsis, mechanical ventilation (MV), immobilization, and systemic administration of corticosteroids (CS). These factors may have additive negative effects on skeletal muscle structure and function, but their respective role alone remain unknown. The primary aim of this study was to examine how CS administration potentiates ventilator and immobilization-related limb muscle dysfunction at the gene level. Comparing biceps femoris gene expression in pigs exposed to MV and CS for 5 days with only MV pigs for the same duration of time showed a distinct deregulation of 186 genes according to microarray. Surprisingly, the decreased force-generation capacity at the single muscle fiber reported in response to the addition of CS administration in mechanically ventilated and immobilized pigs was not associated with an additional upregulation of proteolytic pathways. On the other hand, an altered expression of genes regulating kinase activity, cell cycle, transcription, channel regulation, oxidative stress response, cytoskeletal, sarcomeric, and heat shock protein, as well as protein synthesis at the translational level, appears to play an additive deleterious role for the limb muscle weakness in immobilized ICU patients.
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| 2. |
- Addinsall, Alex B., et al.
(författare)
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Ruxolitinib : A new hope for ventilator-induced diaphragm dysfunction
- 2024
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Ingår i: Acta Physiologica. - : John Wiley & Sons. - 1748-1708 .- 1748-1716. ; 240:5
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Mechanical ventilation (MV) results in diminished diaphragm size and strength, termed ventilator-induced diaphragm dysfunction (VIDD). VID increases dependence, prolongs weaning, and increases discharge mortality rates. The Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is implicated in VIDD, upregulated following MV. JAK/STAT inhibition alleviates chronic muscle wasting conditions. This study aimed to explore the therapeutic potential of Ruxolitinib, an FDA approved JAK1/2 inhibitor (JI) for the treatment of VIDD. Methods: Rats were subjected to 5 days controlled MV (CMV) with and without daily Ruxolitinib gavage. Muscle fiber size and function were assessed. RNAseq, mitochondrial morphology, respirometry, and mass spectrometry were determined. Results: CMV significantly reduced diaphragm size and specific force by 45% (p < 0.01), associated with a two-fold P-STAT3 upregulation (p < 0.001). CMV disrupted mitochondrial content and reduced the oxygen consumption rate (p < 0.01). Expression of the motor protein myosin was unaffected, however CMV alters myosin function via post-translational modifications (PTMs). Daily administration of JI increased animal survival (40% vs. 87%; p < 0.05), restricted P-STAT3 (p < 0.001), and preserved diaphragm size and specific force. JI was associated with preserved mitochondrial content and respiratory function (p < 0.01), and the reversal or augmentation of myosin deamidation PTMs of the rod and head region. Conclusion: JI preserved diaphragm function, leading to increased survival in an experimental model of VIDD. Functional enhancement was associated with maintenance of mitochondrial content and respiration and the reversal of ventilator-induced PTMs of myosin. These results demonstrate the potential of repurposing Ruxolitinib for treatment of VIDD.
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| 3. |
- Akkad, Hazem
(författare)
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Critical illness myopathy : mechanisms and pharmacological interventions
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The human body typically contains over 600 skeletal muscles that make up about 40% of total body weight. These muscles work together to perform functions such as locomotion, breathing, mastication, heat regulation and speech. Skeletal muscles can change their size and protein content in response to endogenous or exogenous signals, including physical, neural or chemical ones. Critically ill patients, usually treated intensively, are prone to developing a condition of muscle wasting and paralysis, called critical illness myopathy (CIM), where limb and truck muscles suffer severe atrophy and loss of force production capacity coupled with a preferential myosin loss, but craniofacial muscles remain less affected. Triggers of CIM are thought to be the exposure to the intensive care unit (ICU) interventions per se, such as unloading, mechanical ventilation (MV) and high doses of certain drugs such as muscle relaxants and glucocorticoids (GCs). The rapidly compromised diaphragm function due to the impact of the ventilator has been given a specific name, ventilator induced diaphragm dysfunction (VIDD). CIM and VIDD have dire consequences and research into their underlying mechanisms is urgently needed. This research is inherently difficult in patients and thus suitable animal models mimicking the ICU condition must be implemented. In this thesis, we used a pig and a rat ICU models with extended periods of immobilization, deep sedation and MV, in which we used different analyses to understand the muscle specific mechanistic differences of the masticatory, limb and the diaphragm muscles. In addition, we explored the effects of two new drugs on skeletal muscles: BGP-15, a chaperone co-inducer and vamorolone, a first-in-class dissociative GC. In paper I, we report that a 5-day GC treatment in the pig ICU model induces numerous transcriptional changes that affect myofiber function in a limb muscle. In paper II, we conclude that the masseter, the main masticatory muscle, is partially protected from CIM effects by several mechanisms that reduce proteolysis, including early heat shock protein (HSPs) activation. In paper III, we report that treatment with BGP-15 activates HSP70 and improves the diaphragm muscle fiber function in young but not old rats. In the last paper, we report differences between the new GC, vamorolone and the traditional GC, prednisolone, in the rat ICU model where the former drug shows less negative effects on fast twitch EDL muscle and both show positive effects on the slow twitch soleus muscle. These results emphasize the uniqueness of each muscle response to ICU interventions and also shed some light on a couple of promising pharmacological interventions that may counteract CIM deleterious effects.
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| 4. |
- Akkad, Hazem, et al.
(författare)
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Masseter Muscle Myofibrillar Protein Synthesis and Degradation in an Experimental Critical Illness Myopathy Model
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:4, s. e92622-
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Tidskriftsartikel (refereegranskat)abstract
- Critical illness myopathy (CIM) is a debilitating common consequence of modern intensive care, characterized by severe muscle wasting, weakness and a decreased myosin/actin (M/A) ratio. Limb/trunk muscles are primarily affected by this myopathy while cranial nerve innervated muscles are spared or less affected, but the mechanisms underlying these muscle-specific differences remain unknown. In this time-resolved study, the cranial nerve innervated masseter muscle was studied in a unique experimental rat intensive care unit (ICU) model, where animals were exposed to sedation, neuromuscular blockade (NMB), mechanical ventilation, and immobilization for durations varying between 6 h and 14d. Gel electrophoresis, immunoblotting, RT-PCR and morphological staining techniques were used to analyze M/A ratios, myofiber size, synthesis and degradation of myofibrillar proteins, and levels of heat shock proteins (HSPs). Results obtained in the masseter muscle were compared with previous observations in experimental and clinical studies of limb muscles. Significant muscle-specific differences were observed, i.e., in the masseter, the decline in M/A ratio and muscle fiber size was small and delayed. Furthermore, transcriptional regulation of myosin and actin synthesis was maintained, and Akt phosphorylation was only briefly reduced. In studied degradation pathways, only mRNA, but not protein levels of MuRF1, atrogin-1 and the autophagy marker LC3b were activated by the ICU condition. The matrix metalloproteinase MMP-2 was inhibited and protective HSPs were up-regulated early. These results confirm that the cranial nerve innervated masticatory muscles is less affected by the ICU-stress response than limb muscles, in accordance with clinical observation in ICU patients with CIM, supporting the model' credibility as a valid CIM model.
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| 5. |
- Cacciani, Nicola, et al.
(författare)
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Chaperone co-inducer BGP-15 mitigates early contractile dysfunction of the soleus muscle in a rat ICU model
- 2020
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Ingår i: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 229:1
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Tidskriftsartikel (refereegranskat)abstract
- Aim Critical illness myopathy (CIM) represents a common consequence of modern intensive care, negatively impacting patient health and significantly increasing health care costs; however, there is no treatment available apart from symptomatic and supportive interventions. The chaperone co-inducer BGP-15 has previously been shown to have a positive effect on the diaphragm in rats exposed to the intensive care unit (ICU) condition. In this study, we aim to explore the effects of BGP-15 on a limb muscle (soleus muscle) in response to the ICU condition. Methods Sprague-Dawley rats were subjected to the ICU condition for 5, 8 and 10 days and compared with untreated sham-operated controls. Results BGP-15 significantly improved soleus muscle fibre force after 5 days exposure to the ICU condition. This improvement was associated with the protection of myosin from post-translational myosin modifications, improved mitochondrial structure/biogenesis and reduced the expression of MuRF1 and Fbxo31 E3 ligases. At longer durations (8 and 10 days), BGP-15 had no protective effect when the hallmark of CIM had become manifest, that is, preferential loss of myosin. Unrelated to the effects on skeletal muscle, BGP-15 had a strong positive effect on survival compared with untreated animals. Conclusions BGP-15 treatment improved soleus muscle fibre and motor protein function after 5 days exposure to the ICU condition, but not at longer durations (8 and 10 days) when the preferential loss of myosin was manifest. Thus, long-term CIM interventions targeting limb muscle fibre/myosin force generation capacity need to consider both the post-translational modifications and the loss of myosin.
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| 6. |
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| 7. |
- Salah, Heba, et al.
(författare)
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The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction
- 2016
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 8:350
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Tidskriftsartikel (refereegranskat)abstract
- Ventilation-induced diaphragm dysfunction (VIDD) is a marked decline in diaphragm function in response to mechanical ventilation, which has negative consequences for individual patients' quality of life and for the health care system, but specific treatment strategies are still lacking. We used an experimental intensive care unit (ICU) model, allowing time-resolved studies of diaphragm structure and function in response to long-term mechanical ventilation and the effects of a pharmacological intervention (the chaperone co-inducer BGP-15). The marked loss of diaphragm muscle fiber function in response to mechanical ventilation was caused by post-translational modifications (PTMs) of myosin. In a rat model, 10 days of BGP-15 treatment greatly improved diaphragm muscle fiber function (by about 100%), although it did not reverse diaphragm atrophy. The treatment also provided protection from myosin PTMs associated with HSP72 induction and PARP-1 inhibition, resulting in improvement of mitochondrial function and content. Thus, BGP-15 may offer an intervention strategy for reducing VIDD in mechanically ventilated ICU patients.
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