How Inflammation Pathways Contribute to Cell Death in Neuro-Muscular Disorders

Salucci, Sara; Stella, Anna Bartoletti; Battistelli, Michela; Burattini, Sabrina; Bavelloni, Alberto; Cocco, Lucio; Gobbi, Pier Giorgio; Faenza, Irene

doi:10.3390/biom11081109

Cited by 13 publications

(7 citation statements)

References 158 publications

(199 reference statements)

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“…While there appears to be no clear signs of muscle-intrinsic inflammatory processes, there is evidence of systemic inflammation. Reported inflammation across different tissues from SMA patients and mice (Deguise and Kothary, 2017 ; Deguise et al, 2017 ; Wan et al, 2018 ; Salucci et al, 2021 ) is suggested to aggravate atrophy of skeletal muscle and promotes cell damage. In muscle from SMA patients, smaller and disorganized myotubes are indicative of impaired growth and maturation (Martínez-Hernández et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

“…SMN depletion leads to the profound loss of motor neurons of the spinal cord (Lefebvre et al, 1997 ) and peripheral organ pathology including the muscle (reviewed in Shababi et al, 2014 ). While the underlying mechanisms are not fully understood, there is growing evidence of cell death pathway activation (Simic et al, 2000 , 2007 ; Shafey et al, 2005 ; Tsai et al, 2006 , 2008 ; Dachs et al, 2011 ; Mutsaers et al, 2011 ; Hayhurst et al, 2012 ; Martínez-Hernández et al, 2013 ; Fayzullina and Martin, 2014 ; Simon et al, 2017 ; Carrasco et al, 2019 ; Courtney et al, 2019 ; Deguise et al, 2020a ; Weissman et al, 2021 ) and inflammation in several tissues in SMA (Deguise and Kothary, 2017 ; Deguise et al, 2017 ; Wan et al, 2018 ; Salucci et al, 2021 ). As such, investigating cell death mechanisms could shed light on the specific pathogenic mechanisms underlying motor neuron death and muscle atrophy.…”

Section: Introductionmentioning

confidence: 99%

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Suppression of the necroptotic cell death pathways improves survival in Smn2B/− mice

Chehadé

Deguise²,

Repentigny³

et al. 2022

Front. Cell. Neurosci.

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Spinal muscular atrophy (SMA) is a monogenic neuromuscular disease caused by low levels of the Survival Motor Neuron (SMN) protein. Motor neuron degeneration is the central hallmark of the disease. However, the SMN protein is ubiquitously expressed and depletion of the protein in peripheral tissues results in intrinsic disease manifestations, including muscle defects, independent of neurodegeneration. The approved SMN-restoring therapies have led to remarkable clinical improvements in SMA patients. Yet, the presence of a significant number of non-responders stresses the need for complementary therapeutic strategies targeting processes which do not rely solely on restoring SMN. Dysregulated cell death pathways are candidates for SMN-independent pathomechanisms in SMA. Receptor-interacting protein kinase 1 (RIPK1) and RIPK3 have been widely recognized as critical therapeutic targets of necroptosis, an important form of programmed cell death. In addition, Caspase-1 plays a fundamental role in inflammation and cell death. In this study, we evaluate the role of necroptosis, particularly RIPK3 and Caspase-1, in the Smn2B/− mouse model of SMA. We have generated a triple mutant (TKO), the Smn2B/−; Ripk3−/−; Casp1−/− mouse. TKO mice displayed a robust increase in survival and improved motor function compared to Smn2B/− mice. While there was no protection against motor neuron loss or neuromuscular junction pathology, larger muscle fibers were observed in TKO mice compared to Smn2B/− mice. Our study shows that necroptosis modulates survival, motor behavior and muscle fiber size independent of SMN levels and independent of neurodegeneration. Thus, small-molecule inhibitors of necroptosis as a combinatorial approach together with SMN-restoring drugs could be a future strategy for the treatment of SMA.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Suppression of the necroptotic cell death pathways improves survival in Smn2B/− mice

Chehadé

Deguise²,

Repentigny³

et al. 2022

Front. Cell. Neurosci.

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“…However, in a number of muscular dystrophies, immune system changes are associated with increases in disease severity [ 75 ]. It is clear that inflammatory processes can lead to neuromuscular cell death thereby causing functional impairments [ 76 ]. Among the best studied changes examining this has been in Duchenne muscular dystrophy (DMD) which involves inflammatory processes which result in an imbalance in macrophage 1 and 2 phenotypes from the innate immune system [ 77 ].…”

Section: Discussionmentioning

confidence: 99%

Blood Transcriptome Profiling Links Immunity to Disease Severity in Myotonic Dystrophy Type 1 (DM1)

Nieuwenhuis

Widomska

Blom³

et al. 2022

IJMS

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The blood transcriptome was examined in relation to disease severity in type I myotonic dystrophy (DM1) patients who participated in the Observational Prolonged Trial In DM1 to Improve QoL- Standards (OPTIMISTIC) study. This sought to (a) ascertain if transcriptome changes were associated with increasing disease severity, as measured by the muscle impairment rating scale (MIRS), and (b) establish if these changes in mRNA expression and associated biological pathways were also observed in the Dystrophia Myotonica Biomarker Discovery Initiative (DMBDI) microarray dataset in blood (with equivalent MIRS/DMPK repeat length). The changes in gene expression were compared using a number of complementary pathways, gene ontology and upstream regulator analyses, which suggested that symptom severity in DM1 was linked to transcriptomic alterations in innate and adaptive immunity associated with muscle-wasting. Future studies should explore the role of immunity in DM1 in more detail to assess its relevance to DM1.

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“…Inflammation and cellular stress responses are closely associated with motor neuron death and ALS pathology [ 29 ]. A previous study has demonstrated that abnormal changes in the immune system owing to the elevation of peripheral NKT cell levels are associated with liver pathology and disease progression in hSOD1 G93A mice [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

Combined Treatment with Herbal Medicine and Drug Ameliorates Inflammation and Metabolic Abnormalities in the Liver of an Amyotrophic Lateral Sclerosis Mouse Model

Park

Yang

2022

Antioxidants

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To date, no effective drugs exist for amyotrophic lateral sclerosis (ALS), although riluzole (RZ) and edaravone have been approved for treatment. We previously reported that Bojungikgi-tang (BJIGT) improved motor activity through anti-inflammatory effects in the muscle and spinal cord of hSOD1G93A mice. Therefore, whether combined treatment with BJIGT and RZ synergistically affects liver function in hSOD1G93A mice was investigated. Two-month-old male hSOD1G93A mice were treated with BJIGT (1 mg/g) and RZ (8 μg/g) administered orally for 5 weeks. Drug metabolism and liver function tests of serum and liver homogenates were conducted. mRNA expression levels of cytochrome P450 (CYP) isozymes, inflammatory cytokines, metabolic factors, and mitochondrial oxidative phosphorylation (OXPHOS) subunits were examined using qPCR and Western blotting. Combined administration of BJIGT and RZ did not alter mRNA expression levels of drug-metabolism-related isozymes (CYP1A2 and CYP3A4) but significantly decreased the activity of liver-function-related enzymes (AST, ALT, ALP, and LDH). Increased expression of inflammatory cytokines (IL-1β, TNF-α, and IL-6) and of intracellular stress-related proteins (Bax, AMPKα, JNK, and p38) was reduced by the combined treatment in hSOD1G93A mice compared to that in control mice. Combined administration reduced the mRNA expression of metabolism-related factors and the expression of OXPHOS subunits. Elevated ATP levels and mitochondrial-fusion-associated protein were decreased after co-administration. Co-administration of BJIGT and RZ did not cause liver damage or toxicity but rather restored liver function in hSOD1G93A mice. This suggests that this combination can be considered a candidate therapeutic agent for ALS.

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How Inflammation Pathways Contribute to Cell Death in Neuro-Muscular Disorders

Cited by 13 publications

References 158 publications

Suppression of the necroptotic cell death pathways improves survival in Smn2B/− mice

Suppression of the necroptotic cell death pathways improves survival in Smn2B/− mice

Blood Transcriptome Profiling Links Immunity to Disease Severity in Myotonic Dystrophy Type 1 (DM1)

Combined Treatment with Herbal Medicine and Drug Ameliorates Inflammation and Metabolic Abnormalities in the Liver of an Amyotrophic Lateral Sclerosis Mouse Model

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