JAK/STAT inhibition augments soleus muscle function in a rat model of critical illness myopathy via regulation of complement C3/3R

Addinsall, Alex B.; Cacciani, Nicola; Akkad, Hazem; Salah, Heba; Tchkonia, Tamara; Kirkland, James L.; Larsson, Lars

doi:10.1113/jp281220

Cited by 15 publications

(23 citation statements)

References 65 publications

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“…In experimental studies, vamorolone reduced the loss of muscle mass, myosin loss, and muscle function in response to 5 days mechanical ventilation and immobilization [ 78 •]. The JAK/STAT inhibitor ruxolitinib attenuated the negative effects of the ICU condition similar to BGP-15 and vamorolone [ 79 •] . BGP-15, vamorolone, and ruxolitinib all have anti-inflammatory effects, albeit at different levels of inflammatory pathways, and in addition to improving muscle function, reducing muscle wasting, and myosin loss, they all improved survival in an experimental ICU model where rats were exposed to immobilization and neuromuscular blockade for 5 days and longer [ 76 •, 78 •].…”

Section: Treatment Optionsmentioning

confidence: 99%

Critical Illness Myopathy: Diagnostic Approach and Resulting Therapeutic Implications

Rodríguez

Larsson

Z'Graggen

2022

Curr Treat Options Neurol

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Purpose of review Critical illness myopathy (CIM) is a common neuro-muscular complication of intensive care treatment associated with increased morbidity and mortality. The current guidelines for diagnosis include clinical and electrophysiological criteria as well as a muscle biopsy, and allow diagnosis only at an advanced stage of the disease. To date, there is no treatment for CIM available, apart from symptomatic and rehabilitative interventions. In this review, we discuss different diagnostic approaches and describe new treatment possibilities for CIM. Recent findings Of the diagnostic approaches evaluated, a new electrophysiological technique for measuring muscle excitability has the greatest potential to allow earlier diagnosis of CIM than the current guidelines do and thereby may facilitate the conduction of future pathophysiological and therapeutic studies. Although clinical trials are still lacking, in animal models, BGP-15, vamorolone, and ruxolitinib have been shown to have anti-inflammatory effects, to reduce muscle wasting and to improve muscle function and survival. Summary In recent years, promising methods for early and confirmatory diagnosis of CIM have been developed, but still need validation. Experimental studies on novel pharmacological interventions show promising results in terms of preventive CIM treatments, but future clinical studies will be needed to study the effectiveness and safety of these drugs.

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Section: Treatment Optionsmentioning

confidence: 99%

Critical Illness Myopathy: Diagnostic Approach and Resulting Therapeutic Implications

Rodríguez

Larsson

Z'Graggen

2022

Curr Treat Options Neurol

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“…Besides upregulating HSPs, BGP-15 also acts as a membrane stabilizer, protects mitochondria, and has antiinflammatory effects (251). The anti-inflammatory effects are of specific interest since activation of the JAK/STAT signaling pathway has been reported in respiratory and limb muscles in both experimental and clinical ICU studies (252,253). The JAK/STAT pathway is a signaling pathway for a wide range of cytokines and growth factors and its activation is a common feature of muscle wasting induced by the cytokine IL-6 (254).…”

Section: Addressing Oxidative and Nitrosative Stressmentioning

confidence: 99%

“…The JAK/STAT pathway is a signaling pathway for a wide range of cytokines and growth factors and its activation is a common feature of muscle wasting induced by the cytokine IL-6 (254). Previous anti-inflammatory interventions with BGP-15, the JAK1/2/STAT3 inhibitor Ruxolitinib, and the prednisolone analog Vamrolone have all shown positive effects on limb and respiratory structure/function (252,253,255).…”

Section: Addressing Oxidative and Nitrosative Stressmentioning

confidence: 99%

Theory: Treatments for Prolonged ICU Patients May Provide New Therapeutic Avenues for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

2021

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We here provide an overview of treatment trials for prolonged intensive care unit (ICU) patients and theorize about their relevance for potential treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Specifically, these treatment trials generally target: (a) the correction of suppressed endocrine axes, notably through a “reactivation” of the pituitary gland's pulsatile secretion of tropic hormones, or (b) the interruption of the “vicious circle” between inflammation, oxidative and nitrosative stress (O&NS), and low thyroid hormone function. There are significant parallels in the treatment trials for prolonged critical illness and ME/CFS; this is consistent with the hypothesis of an overlap in the mechanisms that prevent recovery in both conditions. Early successes in the simultaneous reactivation of pulsatile pituitary secretions in ICU patients—and the resulting positive metabolic effects—could indicate an avenue for treating ME/CFS. The therapeutic effects of thyroid hormones—including in mitigating O&NS and inflammation and in stimulating the adreno-cortical axis—also merit further studies. Collaborative research projects should further investigate the lessons from treatment trials for prolonged critical illness for solving ME/CFS.

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“…Soleus muscles were excised, weighed, and the mid-belly region placed in relaxing solution for muscle bundle preparation [6]. Remaining muscle was snap frozen and stored at -140°C for downstream analysis.…”

Section: Contractile Measurementsmentioning

confidence: 99%

“…To date, cellular and inflammatory stress imbalance, mitochondrial dysfunction, protein degradation, impaired EC-coupling, insulin resistance and hyperglycemia are implicated in the development of CIM, demonstrating the diverse systems effected during critical care (7)(8)(9)(10). This may be explained in part as critical care encompasses CMV and immobilization in critically ill patients of diverse clinical backgrounds and pharmacological interventions.…”

Section: Introductionmentioning

confidence: 99%

Electrical Stimulated GLUT4 Signaling Attenuates Critical Illness-Associated Muscle Wasting

Addinsall

Cacciani

Backéus

et al. 2021

Preprint

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BackgroundCritical illness myopathy (CIM) is a debilitating condition characterized by the preferential loss of the motor protein myosin. CIM is a byproduct of critical care, attributed to impaired recovery, long-term complications, and mortality. CIM pathophysiology is complex, heterogeneous and remains incompletely understood, however loss of mechanical stimuli contributes to critical illness associated muscle atrophy and weakness. Passive mechanical loading (ML) and electrical stimulation (ES) therapies augment muscle mass and function. While having beneficial outcomes, the mechanistic underpinning of these therapies is less known. Therefore, here we aimed to assess the mechanism by which chronic supramaximal ES ameliorates CIM in a unique experimental rat model of critical care.MethodsRats were subjected to 8 days critical care conditions entailing deep sedation, controlled mechanical ventilation, and immobilization with and without direct soleus ES. Muscle size and function were assessed at the single cell level. RNAseq and Western blotting were employed to understand the mechanisms driving ES muscle outcomes in CIM.ResultsFollowing 8 days of controlled mechanical ventilation and immobilization, soleus muscle mass, Myosin:Actin ratio and single muscle fiber maximum force normalized to cross-sectional area (specific force) were reduced by 40-50% (p< 0.0001). ES significantly reduced the loss of soleus muscle fiber cross-sectional area (CSA) and Myosin:Actin ratio by approximately 30% (p< 0.05) yet failed to effect specific force. RNAseq pathway analysis revealed downregulation of insulin signaling in the soleus muscle following critical care and GLUT4 trafficking was reduced by 55% leading to an 85% reduction of muscle glycogen content (p< 0.01). ES promoted phosphofructokinase and insulin signaling pathways to control levels (p< 0.05), consistent with the maintenance of GLUT4 translocation and glycogen levels. AMPK, but not AKT, signaling pathway was stimulated following ES, where the downstream target TBC1D4 increased 3 logFC (p= 0.029) and AMPK-specific P-TBC1D4 levels were increased approximately 2-fold (p= 0.06). Reduction of muscle protein degradation rather than protein synthesis promoted soleus CSA, as ES reduced E3 ubiquitin proteins, Atrogin-1 (p= 0.006) and MuRF1 (p= 0.08) by approximately 50%, downstream of AMPK-FoxO3.ConclusionsES maintained GLUT4 translocation through increased AMPK-TBC1D4 signaling leading to improved muscle glucose homeostasis. Soleus CSA and myosin content was promoted through reduced protein degradation via AMPK-FoxO3 E3 ligases, Atrogin-1 and MuRF1. These results demonstrate chronic supramaximal ES reduces critical care associated muscle wasting, preserved glucose signaling and reduced muscle protein degradation in CIM.

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JAK/STAT inhibition augments soleus muscle function in a rat model of critical illness myopathy via regulation of complement C3/3R

Abstract: JAK/STAT inhibition augments soleus muscle function in a rat model of critical illness myopathy via regulation of complement C3/3R.

Cited by 15 publications

References 65 publications

Critical Illness Myopathy: Diagnostic Approach and Resulting Therapeutic Implications

Critical Illness Myopathy: Diagnostic Approach and Resulting Therapeutic Implications

Theory: Treatments for Prolonged ICU Patients May Provide New Therapeutic Avenues for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Electrical Stimulated GLUT4 Signaling Attenuates Critical Illness-Associated Muscle Wasting

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