Beta-agonist stimulation ameliorates the phenotype of spinal and bulbar muscular atrophy mice and patient-derived myotubes

Milioto, Carmelo; Malena, Adriana; Maino, Eleonora; Polanco, María José; Marchioretti, Caterina; Borgia, Doriana; Pereira, Maria Alice Ornellas; Blaauw, Bert; Lieberman, Andrew P.; Venturini, Roberta; Plebani, Mario; Sambataro, Fabio; Vergani, Lodovica; Pegoraro, Elena; Sorarù, Gian Domenico; Pennuto, Maria

doi:10.1038/srep41046

Cited by 29 publications

(28 citation statements)

References 64 publications

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“…However, motor impairment has not been observed in AR knockout mice (Yeh et al, 2002) or in severe testicular feminisation patients lacking AR function (Batista et al, 2018). Interestingly, recent reports have shown that muscle may play a more prominent part in disease than previously thought and indeed may be a key site of AR toxicity and the development of pathology in SBMA (Cortes et al, 2014a;Lieberman et al, 2014;Milioto et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Deterioration of muscle force and contractile characteristics are early pathological events in spinal and bulbar muscular atrophy mice

Gray

Annan

Dick

et al. 2020

Disease Models &Amp; Mechanisms

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Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's Disease, is a late-onset, X-linked, progressive neuromuscular disease, which predominantly affects males. The pathological hallmarks of the disease are defined by selective loss of spinal and bulbar motor neurons, accompanied by weakness, atrophy and fasciculations of bulbar and limb muscles. SBMA is caused by a CAG repeat expansion in the gene that encodes the androgen receptor (AR) protein. Disease manifestation is androgen dependent and results principally from a toxic gain of AR function. There are currently no effective treatments for this debilitating disease. It is important to understand the course of the disease in order to target therapeutics to key pathological stages. This is especially relevant in disorders such as SBMA, where disease can be identified prior to symptom onset, through family history and genetic testing. To fully characterise the role of muscle in SBMA, we undertook a longitudinal physiological and histological characterisation of disease progression in the AR100 mouse model of SBMA. Our results show that the disease first manifests in skeletal muscle, prior to any motor neuron degeneration, which only occurs in late stage disease. These findings reveal alterations in muscle function, including reduced muscle force and changes in contractile characteristics, are early pathological events in SBMA mice and suggest that muscle-targeted therapeutics may be effective in SBMA.

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Section: Introductionmentioning

confidence: 99%

Deterioration of muscle force and contractile characteristics are early pathological events in spinal and bulbar muscular atrophy mice

Gray

Annan

Dick

et al. 2020

Disease Models &Amp; Mechanisms

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show abstract

“…Pharmacologic intervention to either silence polyQ-expanded AR expression with antisense oligonucleotides (ASOs) in peripheral tissues, specially skeletal muscle (34), or to promote its degradation and stimulate muscle hypertrophy with the insulin-like growth factor 1 and the beta-agonist clenbuterol (35,36) ameliorated disease manifestations, including metabolic defects in muscle (14). These observations further support the idea that not only the MN, but also the skeletal muscle is central to disease and represents a key target-tissue for therapy development.…”

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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“…Gianni Soraru' discussed findings which suggest that beta2-agonist stimulation of muscle may represent a therapeutic avenue for SBMA and describe plans to undertake a clinical trial of clenbuterol in SBMA patients. Treatment of SBMA knock-in mice with clenbuterol started at disease onset ameliorated motor function and extended survival [68] . Moreover, beta2-agonists have been found to be effective in improving motor function without relevant adverse events in a small cohort of SBMA patients [69] .…”

Section: Clinical Trials For Sbmamentioning

confidence: 93%

“…Importantly, genetic and pharmacologic silencing of polyQ-expanded AR expression in skeletal muscle prevented disease manifestations in mouse [5,6] . Moreover, genetic and pharmacologic approaches to stimulate muscle anabolic pathways and inhibit catabolic pathways, and at the same time reduce polyQ-expanded AR toxicity ameliorated disease manifestations in mouse [6,14,24] .…”

Section: Disease Mechanisms: Peripheral Polyq-expanded Ar Mechanisms mentioning

confidence: 99%

241st ENMC international workshop: Towards a European unifying lab for Kennedy's disease. 15–17th February, 2019 Hoofddorp, The Netherlands

Greensmith¹,

Sorarù

Pennuto

2019

Neuromuscular Disorders

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(M. Pennuto). 1 Members of the KD Consortium are listed under Participants at the end of this report. the presentations and discussions that took place during the workshop, which range from disease mechanisms, biomarker discovery, plans for an EU Registry for KD as well as an update on ongoing clinical trials. In addition, a dedicated session on the patient's perspective was presented. Kenneth Fischbeck opened the meeting with an overview of the disease. Kennedy's Disease (KD) also referred to as SBMA is a progressive X-linked neuromuscular disease characterized by bulbar and extremity muscle weakness, atrophy, and fasciculations. Affected males may show signs of androgen insensitivity, such as breast enlargement and reduced fertility. SBMA is caused by expansions of a CAG repeat in the androgen receptor (AR) gene. The disease typically presents in adult males with slowly progressive, relatively symmetrical, lower motor neuron weakness, perioral fasciculations, elevated creatine kinase, and decreased sensory potential amplitudes [1]. Common, but not invariable, manifestations are gynecomastia and a family history consistent with X-linked inheritance. Other non-neuromuscular features include Brugada syndrome [2] , urinary retention [3] , non-alcoholic fatty liver [4] , and fatigue. Primary degeneration of both motor neurons and muscle occurs in SBMA; there are clinical features of denervation and loss of motor neurons in the spinal cord and brainstem, and also increased creatine kinase and histological evidence of muscle fiber degeneration. The disease phenotype can be partially rescued in mouse models with molecular correction in either muscle or the central nervous system [5-7] .

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Beta-agonist stimulation ameliorates the phenotype of spinal and bulbar muscular atrophy mice and patient-derived myotubes

Cited by 29 publications

References 64 publications

Deterioration of muscle force and contractile characteristics are early pathological events in spinal and bulbar muscular atrophy mice

Deterioration of muscle force and contractile characteristics are early pathological events in spinal and bulbar muscular atrophy mice

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

241st ENMC international workshop: Towards a European unifying lab for Kennedy's disease. 15–17th February, 2019 Hoofddorp, The Netherlands

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