Depressed neuromuscular transmission causes weakness in mice lacking BK potassium channels

Wang, Xueyong; Burke, Steven R A; Talmadge, Robert J.; Voss, Andrew A.; Rich, Mark M.

doi:10.1085/jgp.201912526

Cited by 14 publications

(13 citation statements)

References 53 publications

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“…A similar transport of the injected plasmid in ION-03 is possible, and, provided that this is the case, a contribution to the lack of dose dependence in toxicity and in efficacy cannot be excluded. However, in a recently published study, 58 it was the absence of the BK channel and not increased expression that resulted in decreased neuromuscular transmission. Additionally, because URO-902 uses a nonspecific promoter, it is possible that there may be an effect on neurons in the bladder.…”

Section: Further Application To Oabmentioning

confidence: 92%

Gene Therapy for Overactive Bladder: A Review of BK-Channel α-Subunit Gene Transfer

Andersson¹,

Christ²,

Davies³

et al. 2021

TCRM

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A need exists for local (ie, bladder-specific) interventions to treat overactive bladder (OAB) with low risk of unwanted postprocedural outcomes. Gene therapy targeted to leverage endogenous physiology in bladder cells may assist in restoring normal cell and organ function. Herein, we review the potential promise of gene therapy for treating OAB, focusing on gene transfer of URO-902, a non-viral naked plasmid DNA expressing the big potassium (BK) channel. We searched PubMed for articles concerning functional aspects of the BK channel and its potential use for gene transfer as local OAB treatment. Results from preclinical, phase 1, and phase 2 studies of URO-902 for erectile dysfunction and phase 1 studies of URO-902 for OAB are included. The BK channel has been extensively studied; however, URO-902 is the first gene therapy used in clinical trials directed toward treating OAB via the BK channel. In both URO-902 studies, there were no serious adverse events considered treatment related and no adverse events leading to early withdrawal. Both studies included secondary efficacy endpoints with promising results suggesting improvement in OAB symptoms, and quality of life, with use of URO-902 versus placebo. Gene therapy involving the BK channel, such as gene transfer with URO-902, has demonstrated promising safety and efficacy results in women with OAB. Findings warrant further investigation of the use of URO-902 for OAB treatment.

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Section: Further Application To Oabmentioning

confidence: 92%

Gene Therapy for Overactive Bladder: A Review of BK-Channel α-Subunit Gene Transfer

Andersson¹,

Christ²,

Davies³

et al. 2021

TCRM

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“…For gastrocnemius muscle, junctophilin isoform mRNA expression levels were assessed using real-time reverse-transcription PCR analyses with TaqMan gene expression assays (Mm00517485_m1, Mm00517621_m1, and Mm00437762_m1 for Jph1, Jph2, and β2-microglobulin, respectively) from Applied Biosystems Life Technologies Corporation. Jph1 and Jph2 relative expression levels were normalized to β2-microglobulin using the ΔΔCT method ( Livak and Schmittgen, 2001 ) as described previously ( Khedraki et al, 2017 ; Wang et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

A mouse model of Huntington’s disease shows altered ultrastructure of transverse tubules in skeletal muscle fibers

Romer

Metzger

Peraza

et al. 2021

Journal of General Physiology

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Huntington’s disease (HD) is a fatal and progressive condition with severe debilitating motor defects and muscle weakness. Although classically recognized as a neurodegenerative disorder, there is increasing evidence of cell autonomous toxicity in skeletal muscle. We recently demonstrated that skeletal muscle fibers from the R6/2 model mouse of HD have a decrease in specific membrane capacitance, suggesting a loss of transverse tubule (t-tubule) membrane in R6/2 muscle. A previous report also indicated that Cav1.1 current was reduced in R6/2 skeletal muscle, suggesting defects in excitation–contraction (EC) coupling. Thus, we hypothesized that a loss and/or disruption of the skeletal muscle t-tubule system contributes to changes in EC coupling in R6/2 skeletal muscle. We used live-cell imaging with multiphoton confocal microscopy and transmission electron microscopy to assess the t-tubule architecture in late-stage R6/2 muscle and found no significant differences in the t-tubule system density, regularity, or integrity. However, electron microscopy images revealed that the cross-sectional area of t-tubules at the triad were 25% smaller in R6/2 compared with age-matched control skeletal muscle. Computer simulation revealed that the resulting decrease in the R6/2 t-tubule luminal conductance contributed to, but did not fully explain, the reduced R6/2 membrane capacitance. Analyses of bridging integrator-1 (Bin1), which plays a primary role in t-tubule formation, revealed decreased Bin1 protein levels and aberrant splicing of Bin1 mRNA in R6/2 muscle. Additionally, the distance between the t-tubule and sarcoplasmic reticulum was wider in R6/2 compared with control muscle, which was associated with a decrease in junctophilin 1 and 2 mRNA levels. Altogether, these findings can help explain dysregulated EC coupling and motor impairment in Huntington’s disease.

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“…In vivo force measurements were performed on mice anesthetized with isoflurane using a SomnoSuite low‐flow anesthesia system (Kent Scientific), as reported (Wang et al., 2020). Body temperature was monitored with a SomnoSuite temperature probe and maintained at ~35°C using a heat lamp.…”

Section: Methodsmentioning

confidence: 99%

Loss of membrane integrity drives myofiber death in lipin1‐deficient skeletal muscle

et al. 2020

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Mutations in lipin1 are suggested to be a common cause of massive rhabdomyolysis episodes in children; however, the molecular mechanisms involved in the regulation of myofiber death caused by the absence of lipin1 are not fully understood. Loss of membrane integrity is considered as an effective inducer of cell death in muscular dystrophy. In this study, we utilized a mouse line with selective homozygous lipin1 deficiency in the skeletal muscle (Lipin1 Myf5cKO ) to determine the role of compromised membrane integrity in the myofiber death in lipin1‐deficient muscles. We found that Lipin1 Myf5cKO muscles had significantly elevated proapoptotic factors (Bax, Bak, and cleaved caspase‐9) and necroptotic proteins such as RIPK1, RIPK3, and MLKL compared with WT mice. Moreover, Lipin1 Myf5cKO muscle had significantly higher membrane disruptions, as evidenced by increased IgG staining and elevated uptake of Evans Blue Dye (EBD) and increased serum creatine kinase activity in Lipin1 Myf5cKO muscle fibers. EBD‐positive fibers were strongly colocalized with apoptotic or necroptotic myofibers, suggesting an association between compromised plasma membrane integrity and cell death pathways. We further show that the absence of lipin1 leads to a significant decrease in the absolute and specific muscle force (normalized to muscle mass). Our work indicates that apoptosis and necroptosis are associated with a loss of membrane integrity in Lipin1 Myf5cKO muscle and that myofiber death and dysfunction may cause a decrease in contractile force.

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Depressed neuromuscular transmission causes weakness in mice lacking BK potassium channels

Cited by 14 publications

References 53 publications

Gene Therapy for Overactive Bladder: A Review of BK-Channel α-Subunit Gene Transfer

Gene Therapy for Overactive Bladder: A Review of BK-Channel α-Subunit Gene Transfer

A mouse model of Huntington’s disease shows altered ultrastructure of transverse tubules in skeletal muscle fibers

Loss of membrane integrity drives myofiber death in lipin1‐deficient skeletal muscle

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