Molecular Characterization of Skeletal Muscle Dysfunction in Sigma 1 Receptor (Sigmar1) Knockout Mice

Aishwarya, Richa; Abdullah, Chowdhury S.; Remex, Naznin Sultana; Alam, Shafiul; Morshed, Mahboob; Nitu, Sadia; Hartman, Brandon; King, Judy A.; Bhuiyan, Mohammad Alfrad Nobel; Orr, A. Wayne; Kevil, Christopher G.; Bhuiyan, Md. Shenuarin

doi:10.1016/j.ajpath.2021.10.003

Cited by 8 publications

(14 citation statements)

References 72 publications

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“…Paraffin-embedded 5 µm thin tissue sections from human and mouse lung tissues were stained for immunofluorescence microscopy to determine Sigmar1’s presence and expression in lungs, as previously described ( Bhuiyan et al, 2013b ; Aishwarya et al, 2022 ). Briefly, the lung sections were deparaffinized, rehydrated, and antigen-unmasked by boiling at 100°C for 30 min with 10 mmol/L sodium citrate buffer (pH 6.0).…”

Section: Methodsmentioning

confidence: 99%

“…Total proteins were isolated from the lung tissues of Wt and Sigmar1 −/− mice and whole cell tissue lysates were prepared for Western blotting following previously described protocol ( Abdullah et al, 2018 ; Abdullah et al, 2020 ; Aishwarya et al, 2022 ). The harvested lung tissues were lysed in an ice-cold lysis buffer called Cell Lytic M (Sigma-Aldrich, St. Louis, MO) supplemented with Complete Protease Inhibitor Cocktail (Roche, Basel, Switzerland) using a bead homogenizer and subsequent sonication of the homogenized material.…”

Section: Methodsmentioning

confidence: 99%

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Sigmar1 ablation leads to lung pathological changes associated with pulmonary fibrosis, inflammation, and altered surfactant proteins levels

et al. 2023

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Sigma1 receptor protein (Sigmar1) is a small, multifunctional molecular chaperone protein ubiquitously expressed in almost all body tissues. This protein has previously shown its cardioprotective roles in rodent models of cardiac hypertrophy, heart failure, and ischemia-reperfusion injury. Extensive literature also suggested its protective functions in several central nervous system disorders. Sigmar1’s molecular functions in the pulmonary system remained unknown. Therefore, we aimed to determine the expression of Sigmar1 in the lungs. We also examined whether Sigmar1 ablation results in histological, ultrastructural, and biochemical changes associated with lung pathology over aging in mice. In the current study, we first confirmed the presence of Sigmar1 protein in human and mouse lungs using immunohistochemistry and immunostaining. We used the Sigmar1 global knockout mouse (Sigmar1−/−) to determine the pathophysiological role of Sigmar1 in lungs over aging. The histological staining of lung sections showed altered alveolar structures, higher immune cells infiltration, and upregulation of inflammatory markers (such as pNFκB) in Sigmar1−/− mice compared to wildtype (Wt) littermate control mice (Wt). This indicates higher pulmonary inflammation resulting from Sigmar1 deficiency in mice, which was associated with increased pulmonary fibrosis. The protein levels of some fibrotic markers, fibronectin, and pSMAD2 Ser 245/250/255 and Ser 465/467, were also elevated in mice lungs in the absence of Sigmar1 compared to Wt. The ultrastructural analysis of lungs in Wt mice showed numerous multilamellar bodies of different sizes with densely packed lipid lamellae and mitochondria with a dark matrix and dense cristae. In contrast, the Sigmar1−/− mice lung tissues showed altered multilamellar body structures in alveolar epithelial type-II pneumocytes with partial loss of lipid lamellae structures in the lamellar bodies. This was further associated with higher protein levels of all four surfactant proteins, SFTP-A, SFTP-B, SFTP-C, and SFTP-D, in the Sigmar1−/− mice lungs. This is the first study showing Sigmar1’s expression pattern in human and mouse lungs and its association with lung pathophysiology. Our findings suggest that Sigmar1 deficiency leads to increased pulmonary inflammation, higher pulmonary fibrosis, alterations of the multilamellar body stuructures, and elevated levels of lung surfactant proteins.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Sigmar1 ablation leads to lung pathological changes associated with pulmonary fibrosis, inflammation, and altered surfactant proteins levels

et al. 2023

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“…Mutations in the sigma-1 gene are associated with distal neuropathies with skeletal muscle dysfunction, such as muscle wasting, but there are no reports on the mechanism of the sigma-1 receptor and rhabdomyolysis. New research showed the presence of abnormal mitochondria and derangements in dystrophin localisation in skeletal muscles from sigma-1 knockout mice 21. It suggests that sigma-1 activation plays an important role in maintaining the structural and functional aspects of healthy skeletal muscle.…”

Section: Discussionmentioning

confidence: 99%

Rhabdomyolysis in a male adolescent associated with monotherapy of fluvoxamine

et al. 2022

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Rhabdomyolysis is a syndrome resulting from striated muscular breakdown, which may occur due to drug therapy with agents such as selective serotonin reuptake inhibitors (SSRIs). Although studies have shown that fluvoxamine can rarely cause myalgia, there are no reported cases of rhabdomyolysis due to fluvoxamine monotherapy. Here we describe a case of rhabdomyolysis due to fluvoxamine monotherapy for obsessive-compulsive disorder. The young adolescent developed pain in the extremities, and an increase in serum creatine kinase (CK) and myoglobin during fluvoxamine treatment. These adverse reactions were reversed immediately after the medicine was changed to another SSRI—sertraline. This is the first reported case of fluvoxamine-associated rhabdomyolysis. It is advisable to determine serum CK levels before starting fluvoxamine treatment, and then at regular intervals, to avoid the occurrence of severe acute kidney injury with possible life-threatening complications.

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“…Grip strength measurements were used to evaluate skeletal muscle endurance capacity. The forelimb grip strength of the mice (Wt and G93A*SOD1) was assessed, as described previously [50][51][52]. Briefly, we acclimated the mice for at least 10 min before the experiment.…”

Section: Muscle Endurance Capacitymentioning

confidence: 99%

“…For the histological analysis of the muscle sections, we used serial sections of 5µm cut from paraffin-embedded blocks of muscles (Wt and G93A*SOD1 mice). We deparaffinized and hydrated the muscle sections, followed by staining with Picro-Sirius Red [52,[54][55][56] and H&E (H&E staining kit; H3502; Vector Laboratories) using the manufacturer's protocol. In bright-field mode, stained slides were imaged in an investigator-blinded manner using Olympus BX40 microscope (Tokyo, Japan).…”

Section: Histological Analysesmentioning

confidence: 99%

Pathological Sequelae Associated with Skeletal Muscle Atrophy and Histopathology in G93A*SOD1 Mice

Aishwarya

Abdullah

Remex

et al. 2023

Muscles

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Amyotrophic lateral sclerosis (ALS) is a complex systemic disease that primarily involves motor neuron dysfunction and skeletal muscle atrophy. One commonly used mouse model to study ALS was generated by transgenic expression of a mutant form of human superoxide dismutase 1 (SOD1) gene harboring a single amino acid substitution of glycine to alanine at codon 93 (G93A*SOD1). Although mutant-SOD1 is ubiquitously expressed in G93A*SOD1 mice, a detailed analysis of the skeletal muscle expression pattern of the mutant protein and the resultant muscle pathology were never performed. Using different skeletal muscles isolated from G93A*SOD1 mice, we extensively characterized the pathological sequelae of histological, molecular, ultrastructural, and biochemical alterations. Muscle atrophy in G93A*SOD1 mice was associated with increased and differential expression of mutant-SOD1 across myofibers and increased MuRF1 protein level. In addition, high collagen deposition and myopathic changes sections accompanied the reduced muscle strength in the G93A*SOD1 mice. Furthermore, all the muscles in G93A*SOD1 mice showed altered protein levels associated with different signaling pathways, including inflammation, mitochondrial membrane transport, mitochondrial lipid uptake, and antioxidant enzymes. In addition, the mutant-SOD1 protein was found in the mitochondrial fraction in the muscles from G93A*SOD1 mice, which was accompanied by vacuolized and abnormal mitochondria, altered OXPHOS and PDH complex protein levels, and defects in mitochondrial respiration. Overall, we reported the pathological sequelae observed in the skeletal muscles of G93A*SOD1 mice resulting from the whole-body mutant-SOD1 protein expression.

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Molecular Characterization of Skeletal Muscle Dysfunction in Sigma 1 Receptor (Sigmar1) Knockout Mice

Cited by 8 publications

References 72 publications

Sigmar1 ablation leads to lung pathological changes associated with pulmonary fibrosis, inflammation, and altered surfactant proteins levels

Sigmar1 ablation leads to lung pathological changes associated with pulmonary fibrosis, inflammation, and altered surfactant proteins levels

Rhabdomyolysis in a male adolescent associated with monotherapy of fluvoxamine

Pathological Sequelae Associated with Skeletal Muscle Atrophy and Histopathology in G93A*SOD1 Mice

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