記述言語：英語   出版者・発行元：Journal of Cachexia, Sarcopenia and Muscle  

Background: Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by the expansion of trinucleotide cytosine–adenine–guanine (CAG) repeats, which encodes a polyglutamine (polyQ) tract in the androgen receptor (AR) gene. Recent evidence suggests that, in addition to motor neuron degeneration, defective skeletal muscles are also the primary contributors to the pathogenesis in SBMA. While benefits of physical exercise have been suggested in SBMA, underlying mechanism remains elusive. Methods: We investigated the effect of running exercise in a transgenic mouse model of SBMA carrying human AR with 97 expanded CAGs (AR97Q). We assigned AR97Q mice to exercise and sedentary control groups, and mice in the exercise group received 1-h forced running wheel (5 m/min) 5 days a week for 4 weeks during the early stage of the disease. Motor function (grip strength and rotarod performance) and survival of each group were analysed, and histopathological and biological features in skeletal muscles and motor neurons were evaluated. Results: AR97Q mice in the exercise group showed improvement in motor function (~40% and ~50% increase in grip strength and rotarod performance, respectively, P < 0.05) and survival (median survival 23.6 vs. 16.7 weeks, P < 0.05) with amelioration of neuronal and muscular histopathology (~1.4-fold and ~2.8-fold increase in motor neuron and muscle fibre size, respectively, P < 0.001) compared to those in the sedentary group. Nuclear accumulation of polyQ-expanded AR in skeletal muscles and motor neurons was suppressed in the mice with exercise compared to the sedentary mice (~50% and ~30% reduction in 1C2-positive cells in skeletal muscles and motor neurons, respectively, P < 0.05). We found that the exercise activated 5′-adenosine monophosphate-activated protein kinase (AMPK) signalling and inhibited mammalian target of rapamycin pathway that regulates protein synthesis in skeletal muscles of SBMA mice. Pharmacological activation of AMPK inhibited protein synthesis and reduced polyQ-expanded AR proteins in C2C12 muscle cells. Conclusions: Our findings suggest the therapeutic potential of exercise-induced effect via AMPK activation in SBMA.

DOI： 10.1002/jcsm.13344

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Scopus

PubMed

記述言語：日本語   出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1416202469

PubMed

CiNii Research

記述言語：英語   出版者・発行元：Orphanet Journal of Rare Diseases  

Background: A rare muscle disease, GNE myopathy is caused by mutations in the GNE gene involved in sialic acid biosynthesis. Our recent phase II/III study has indicated that oral administration of aceneuramic acid to patients slows disease progression. Methods: We conducted a phase III, randomized, placebo-controlled, double-blind, parallel-group, multicenter study. Participants were assigned to receive an extended-release formulation of aceneuramic acid (SA-ER) or placebo. Changes in muscle strength and function over 48 weeks were compared between treatment groups using change in the upper extremity composite (UEC) score from baseline to Week 48 as the primary endpoint and the investigator-assessed efficacy rate as the key secondary endpoint. For safety, adverse events, vital signs, body weight, electrocardiogram, and clinical laboratory results were monitored. Results: A total of 14 patients were enrolled and given SA-ER (n = 10) or placebo (n = 4) tablets orally. Decrease in least square mean (LSM) change in UEC score at Week 48 with SA-ER (− 0.115 kg) was numerically smaller as compared with placebo (− 2.625 kg), with LSM difference (95% confidence interval) of 2.510 (− 1.720 to 6.740) kg. In addition, efficacy was higher with SA-ER as compared with placebo. No clinically significant adverse events or other safety concerns were observed. Conclusions: The present study reproducibly showed a trend towards slowing of loss of muscle strength and function with orally administered SA-ER, indicating supplementation with sialic acid might be a promising replacement therapy for GNE myopathy. Trial registration number: ClinicalTrials.gov (NCT04671472).

DOI： 10.1186/s13023-023-02850-y

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PubMed

記述言語：英語   出版者・発行元：Neurology  

Background and ObjectivesTo assess the clinical and electrophysiologic features of female carriers and early-stage male patients with spinal and bulbar muscular atrophy (SBMA) to elucidate the early pathophysiologic changes of the disease.MethodsFemale carriers, early-stage male patients with SBMA, and age-matched male and female healthy controls were recruited. The results of motor functional scales, motor unit number estimation, dual-energy X-ray absorptiometry, and peripheral blood tests were compared between female carriers and healthy female controls and between patients with SBMA and healthy male controls. EMG was also investigated in female carriers.ResultsWe enrolled 21 female carriers and 11 early-stage male patients. Seventeen female and 14 male age-matched healthy controls were also enrolled. Female carriers experienced early-stage symptoms such as muscle cramps more frequently than healthy female controls. Decreased motor unit number estimation and EMG abnormalities including high amplitude or polyphasic potentials were observed in female carriers together with mild muscle weakness in neck flexion and a slow walking speed. Changes of muscle-related markers, including serum creatine kinase and dual-energy X-ray absorptiometry, were clearly detected in early-stage male patients with SBMA, but not in female carriers.DiscussionThe present study revealed that female carriers of SBMA manifest mild muscular weakness associated with changes in neurogenic biomarkers. Conversely, male patients showed neurogenic and myopathic changes even at the early stage. These results suggest a testosterone-independent neurodegenerative pathophysiology in female SBMA carriers.

DOI： 10.1212/WNL.0000000000201342

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PubMed

記述言語：英語   出版者・発行元：Journal of Neuromuscular Diseases  

Background: GNE myopathy is an ultra-rare muscle disease characterized by a reduction in the synthesis of sialic acid derived from pathogenic variants in the GNE gene. No treatment has been established so far. Objective: We evaluated the safety and efficacy of oral supplementation of aceneuramic acid in patients with GNE myopathy. Methods: This multicenter, placebo-controlled, double-blind study comprised genetically confirmed GNE myopathy patients in Japan who were randomly assigned into treatment groups of sialic acid-extended release (SA-ER) tablets (6 g/day for 48 weeks) or placebo groups (4:1). The primary endpoint of effectiveness was set as the change in total upper limb muscle strength (upper extremity composite [UEC] score) from the start of administration to the final evaluation time point. Results: Among the 20 enrolled patients (SA-ER group, 16; placebo group, 4), 19 completed this 48-week study. The mean value of change in UEC score (95% confidence interval [CI]) at 48 weeks was -0.1 kg (-2.1 to 2.0) in the SA-ER group and -5.1 kg (-10.4 to 0.3) in the placebo group. The least squares mean difference (95% CI) between the groups in the covariance analysis was 4.8 kg (-0.3 to 9.9; P = 0.0635). The change in UEC score at 48 weeks was significantly higher in the SA-ER group compared with the placebo group (P = 0.0013) in the generalized estimating equation test repeated measurement analysis. In one patient in the SA-ER group, who was found to be pregnant 2 weeks after drug administration fetal death with tangled umbilical cord occurred at 13 weeks after the discontinuation of treatment. No other serious adverse effects were observed. Conclusions: The present study indicates that oral administration of SA-ER tablets is effective and safe in patients with GNE myopathy in Japan.

DOI： 10.3233/JND-230029

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PubMed