Modulation of the Neuregulin 1/ErbB system after skeletal muscle denervation and reinnervation

Morano, Michela; Ronchi, Giulia; Nicolò, Valentina; Fornasari, Benedetta Elena; Crosio, Alessandro; Perroteau, Isabelle; Geuna, Stefano; Gambarotta, Giovanna; Raimondo, Stefania

doi:10.1038/s41598-018-23454-8

Cited by 25 publications

(19 citation statements)

References 36 publications

(50 reference statements)

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“…These factors are often assessed as markers of denervation in adult skeletal muscle (Rowan et al, 2012;Sekiguchi et al, 2012;Hendrickse et al, 2018;Sonjak et al, 2019). The reduction in expression of these transcripts following RT supports our laboratory's previous findings (Kelly et al, 2018a) and provides direction toward other possible targets for assessment in muscle denervation-reinnervation cycling, including ERBB3 (Erb-B2 receptor tyrosine kinase 3) (Morano et al, 2018) and MAGED1 (melanoma antigen gene family D1) (Magnusson et al, 2005). Like these denervation markers, expression of genes linked to neural apoptosis was increased with aging and reduced with exercise.…”

Section: Genes Linked To Dynamics Of Denervation and Neural Apoptosissupporting

confidence: 81%

Rehabilitative Impact of Exercise Training on Human Skeletal Muscle Transcriptional Programs in Parkinson’s Disease

Lavin

Sealfon

et al. 2020

Front. Physiol.

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Parkinson's disease (PD) is the most common motor neurodegenerative disease, and neuromuscular function deficits associated with PD contribute to disability. Targeting these symptoms, our laboratory has previously evaluated 16-week high-intensity resistance exercise as rehabilitative training (RT) in individuals with PD. We reported significant improvements in muscle mass, neuromuscular function (strength, power, and motor unit activation), indices of neuromuscular junction integrity, total and motor scores on the unified Parkinson's disease rating scale (UPDRS), and total and sub-scores on the 39-item PD Quality of Life Questionnaire (PDQ-39), supporting the use of RT to reverse symptoms. Our objective was to identify transcriptional networks that may contribute to RT-induced neuromuscular remodeling in PD. We generated transcriptome-wide skeletal muscle RNA-sequencing in 5 participants with PD [4M/1F, 67 ± 2 years, Hoehn and Yahr stages 2 (n = 3) and 3 (n = 2)] before and after 16-week high intensity RT to identify transcriptional networks that may in part underpin RT-induced neuromuscular remodeling in PD. Following RT, 304 genes were significantly upregulated, notably related to remodeling and nervous system/muscle development. Additionally, 402 genes, primarily negative regulators of muscle adaptation, were downregulated. We applied the recently developed Pathway-Level Information ExtractoR (PLIER) method to reveal coordinated gene programs (as latent variables, LVs) that differed in skeletal muscle among young (YA) and old (OA) healthy adults and PD (n = 12 per cohort) at baseline and in PD pre-vs. post-RT. Notably, one LV associated with angiogenesis, axon guidance, and muscle remodeling was significantly lower in PD than YA at baseline and was significantly increased by exercise. A different LV annotated to denervation, autophagy, and apoptosis was increased in both PD and OA relative to YA and was also reduced by 16-week RT in PD. Thus, this analysis identified two novel skeletal

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Section: Genes Linked To Dynamics Of Denervation and Neural Apoptosissupporting

confidence: 81%

Rehabilitative Impact of Exercise Training on Human Skeletal Muscle Transcriptional Programs in Parkinson’s Disease

Lavin

Sealfon

et al. 2020

Front. Physiol.

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“…Further, ERBB4 mRNA was strongly downregulated in DMD muscle (−6.2-fold; adjusted P = 9.5 × 10 −6 ). ERBB4 is a cell-surface receptor neuregulin, and the NRG1/ERBB4 pathway has been extensively studied in hypoxia, TGF-β and fibrosis in the heart, kidney and neuronal cells where it plays a protective role and can be downregulated in disease states ( 38 , 39 ). In skeletal muscle, it appears important for mitochondrial function, and deficiency can lead to defects in oxidative phosphorylation ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

Serum biomarkers associated with baseline clinical severity in young steroid-naïve Duchenne muscular dystrophy boys

Dang

Ziemba

Clemens

et al. 2020

Human Molecular Genetics

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Duchenne muscular dystrophy (DMD) is caused by loss of dystrophin in muscle, and while all patients share the primary gene and biochemical defect, there is considerable patient-patient variability in clinical symptoms. We sought to develop multivariate models of serum protein biomarkers that explained observed variation, using functional outcome measures as proxies for severity. Serum samples from 39 steroid-naïve DMD boys 4 to < 7 years enrolled into a clinical trial of vamorolone were studied (NCT02760264). Four assessments of gross motor function were carried out for each participant over a 6-week interval and their mean was used as response for biomarker models. Weighted correlation network analysis was used for unsupervised clustering of 1305 proteins quantified using SOMAscan® aptamer profiling to define highly representative and connected proteins. Multivariate models of biomarkers were obtained for time to stand performance (strength phenotype; 17 proteins) and 6-minute walk performance (endurance phenotype; 17 proteins) including some shared proteins. Identified proteins were tested with associations of mRNA expression with histological severity of muscle from dystrophinopathy patients (n = 28) and normal controls (n = 6). Strong associations predictive of both clinical and histological severity were found for ERBB4 (reductions in both blood and muscle with increasing severity), SOD1 (reductions in muscle and increases in blood with increasing severity), and CNTF (decreased levels in blood and muscle with increasing severity). We show that performance of DMD boys was effectively modeled with serum proteins, with proximal strength associated with growth and remodeling pathways, and muscle endurance centered on TGFβ and fibrosis pathways in muscle.

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“…NRG-1 contains an epidermal growth factor-(EGF-) like domain that can bind to and activate receptor tyrosine kinases of the ErbB family (ErbB2, ErbB3, and ErbB4), exerting its role in cell survival, proliferation, migration, and differentiation [15,16]. All of the ErbB receptors are mainly present at the NMJ [17], and NRG-1 acts as a medium between terminal Schwann cells and motor axons, between motor axons and muscles, and between different muscle fibres [18,19]. Previous studies have shown that sepsis can induce a reduction in NRG-1 in the skeletal muscle system [20,21].…”

Section: Introductionmentioning

confidence: 99%

Neuregulin-1β Protects the Rat Diaphragm during Sepsis against Oxidative Stress and Inflammation by Activating the PI3K/Akt Pathway

Liu

Weng

Yao

et al. 2020

Oxidative Medicine and Cellular Longevity

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Sepsis-induced diaphragm dysfunction (SIDD) which is mainly characterized by decrease in diaphragmatic contractility has been identified to cause great harms to patients. Therefore, there is an important and pressing need to find effective treatments for improving SIDD. In addition, acetylcholinesterase (AChE) activity is a vital property of the diaphragm, so we evaluated both diaphragmatic contractility and AChE activity. Though neuregulin-1β (NRG-1β) is known to exert organ-protective effects in some inflammatory diseases, little is known about the potential of NRG-1β therapy in the diaphragm during sepsis. Our study was aimed at exploring the effects of NRG-1β application on diaphragmatic contractility and AChE activity during sepsis. Proinflammatory cytokines, muscle injury biomarkers in serum, contractile force, AChE activity, proinflammatory cytokines, oxidative parameters, histological condition, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and expression of phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB/Akt) signaling proteins in the diaphragm were measured and compared between nonseptic and septic groups with or without NRG-1β treatment. In vitro, the effects of NRG-1β on reactive oxygen species (ROS) production in the lipopolysaccharide- (LPS-) stimulated L6 rat muscle skeletal cells with or without the Akt inhibitor MK-2206 were detected. NRG-1β inhibited proinflammatory cytokine release and muscle injury biomarkers soaring in serum and improved the sepsis-induced diaphragm dysfunction and AChE activity decrease significantly during sepsis. Meanwhile, the inflammatory response, oxidative stress, pathological impairment, and cell apoptosis in the diaphragm were mitigated by NRG-1β. And NRG-1β activated the PI3K/Akt signaling in the diaphragm of septic rats. Elevated ROS production in the LPS-stimulated L6 rat skeletal muscle cells was reduced after treatment with NRG-1β, while MK-2206 blocked these effects of NRG-1β. In conclusion, our findings underlined that NRG-1β could reduce circulating levels of proinflammatory cytokines in rats with sepsis, adjust diaphragmatic proinflammatory cytokine level, mitigate diaphragmatic oxidative injury, and lessen diaphragm cell apoptosis, thereby improving diaphragmatic function, and play a role in diaphragmatic protection by activating PI3K/Akt signaling.

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Modulation of the Neuregulin 1/ErbB system after skeletal muscle denervation and reinnervation

Cited by 25 publications

References 36 publications

Rehabilitative Impact of Exercise Training on Human Skeletal Muscle Transcriptional Programs in Parkinson’s Disease

Rehabilitative Impact of Exercise Training on Human Skeletal Muscle Transcriptional Programs in Parkinson’s Disease

Serum biomarkers associated with baseline clinical severity in young steroid-naïve Duchenne muscular dystrophy boys

Neuregulin-1β Protects the Rat Diaphragm during Sepsis against Oxidative Stress and Inflammation by Activating the PI3K/Akt Pathway

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