An open trial of long‐term testosterone suppression in spinal and bulbar muscular atrophy

Yamamoto, Tomotaka; Yokota, Kazuhiko; Amao, Rie; Maéno, Takashi; Haga, Nobuhiko; Taguri, Masataka; Ohtsu, Hiroshi; Ichikawa, Yaeko; Goto, Jun; Tsuji, Shoji

doi:10.1002/mus.23759

Cited by 12 publications

(12 citation statements)

References 23 publications

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“…While these clinical trials identified potentially beneficial outcomes from reducing AR activation (Fernandez-Rhodes et al, 2011; Katsuno et al, 2010), the global reduction in AR function can have deleterious effects on the mental well-being of patients (Fernandez-Rhodes et al, 2011). Moreover, in recent clinical trials (Rhodes et al, 2009; Yamamoto et al, 2013), the observed correlation between muscle strength and testosterone levels suggests that the anabolic effects of AR function in muscle should be considered in the development of effective therapies for SBMA.…”

Section: Discussionmentioning

confidence: 99%

Preventing the Androgen Receptor N/C Interaction Delays Disease Onset in a Mouse Model of SBMA

et al. 2015

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Summary Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by a polyglutamine expansion in the androgen receptor (AR) and is associated with misfolding and aggregation of the mutant AR. We investigated the role of an interdomain interaction between the amino (N)-terminal FxxLF motif and carboxyl (C)-terminal AF-2 domain in a mouse model of SBMA. Male transgenic mice expressing polyQ-expanded AR with a mutation in the FxxLF motif (F23A) to prevent the N/C interaction displayed substantially improved motor function, compared to N/C-intact AR-expressing mice, and showed reduced pathological features of SBMA. Serine 16 phosphorylation was substantially enhanced by the F23A mutation; moreover, the protective effect of AR F23A was dependent on this phosphorylation. These results reveal an important role for the N/C interaction on disease onset in mice, and suggest that targeting AR conformation could be a therapeutic strategy for patients with SBMA.

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Section: Discussionmentioning

confidence: 99%

Preventing the Androgen Receptor N/C Interaction Delays Disease Onset in a Mouse Model of SBMA

et al. 2015

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“…A key factor contributing to the toxic GOF of polyQ-AR is the deposition of the disease protein into micro-aggregates and inclusion bodies, and specific types of polyQ-AR-positive aggregates have been linked to neurotoxicity in vitro and in vivo (12,(16)(17)(18)(19). Although the androgen-dependent nature of disease and experimental evidence support chemical and physical castration as a therapeutic strategy for SBMA (10,11,13), clinical trials based on this approach showed benefits limited to a subset of patients (20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Polyglutamine-expanded androgen receptor disrupts muscle triad, calcium dynamics and the excitation-contraction coupling gene expression program

Chivet

Marchioretti

Pirazzini

et al. 2019

Preprint

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Spinal and bulbar muscular atrophy (SBMA) is caused by polyglutamine (polyQ) expansions in the androgen receptor (AR) gene. Although clinical and experimental evidence highlight a primary role for skeletal muscle in the onset, progression, and outcome of disease, the pathophysiological and molecular processes underlying SBMA muscle atrophy are poorly understood. Here we show that polyQ-expanded AR alters intrinsic muscle force generation before denervation. Reduced muscle force was associated with a switch in fiber-type composition, disrupted muscle striation, altered calcium (Ca ++ ) dynamics in response to muscle contraction, and aberrant expression of excitation-contraction coupling (ECC) machinery genes in transgenic, knock-in and inducible SBMA mice and patients. Importantly, treatment to suppress polyQ-expanded AR toxicity restored ECC gene expression back to normal. Suppression of AR activation by surgical castration elicited similar ECC gene expression changes in normal mice, suggesting that AR regulates the expression of these genes in physiological conditions. Bioinformatic analysis revealed the presence of androgen-responsive elements on several genes involved in muscle function and homeostasis, and experimental evidence showed AR-dependent regulation of expression and promoter occupancy of the most up-regulated gene from transcriptomic analysis in SBMA muscle, i.e. sarcolipin, a key ECC gene. These observations reveal an unpredicted role for AR in the regulation of expression of genes involved in muscle contraction and Ca ++ dynamics, a level of muscle function regulation that is disrupted in SBMA muscle, yet restored by pharmacologic treatment.

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“…It also should be pointed out that an open-label study with leuprorelin in 16 patients with SBMA demonstrated no improvement in muscle weakness 12. It is suspected that lack of androgens may cause muscle weakness and may even facilitate further neuronal degeneration 13.…”

Section: No Testosterone For Spinal and Bulbar Muscular Atrophy (Sbma)mentioning

confidence: 99%

Long-term treatment with leuprorelin for spinal and bulbar muscular atrophy

Mitsumoto

2017

J Neurol Neurosurg Psychiatry

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An open trial of long‐term testosterone suppression in spinal and bulbar muscular atrophy

Abstract: Leuprorelin was not effective in this small long-term treatment trial in SBMA. The possibility that earlier treatment might be beneficial may deserve further study.

Cited by 12 publications

References 23 publications

Preventing the Androgen Receptor N/C Interaction Delays Disease Onset in a Mouse Model of SBMA

Preventing the Androgen Receptor N/C Interaction Delays Disease Onset in a Mouse Model of SBMA

Polyglutamine-expanded androgen receptor disrupts muscle triad, calcium dynamics and the excitation-contraction coupling gene expression program

Long-term treatment with leuprorelin for spinal and bulbar muscular atrophy

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