Local Vibration Stimuli Induce Mechanical Stress-Induced Factors and Facilitate Recovery From Immobilization-Induced Oxidative Myofiber Atrophy in Rats.

Muscle atrophy can be caused by unloading stress such as microgravity environments or cast immobilization. Therapies for such disuse muscle atrophy and their underlying mechanisms are incompletely understood. Here, we investigated the therapeutic effects of local vibration stimulation on immobilization-induced skeletal muscle atrophy. A rat model was made by placing the left hindlimb in a cast for 1 week, leading to oxidative myofiber atrophy without myopathic changes in soleus skeletal muscle. Vibration stimulus (90 Hz, 15 min) to the plantar fascia of the atrophic hindlimb was performed once a day using a hand-held vibration massager after removal of a cast at the end of the immobilization period. After 2 weeks, rats were dissected, and quantitative analysis of the cross-sectional areas of soleus myofibers was performed. The results revealed that vibration induced significant recovery from disuse muscle atrophy, compared with untreated immobilized samples. Furthermore, vibration treatment suppressed the fiber transition from slow to fast fiber types compared with vibration-untreated immobilized samples. Western blotting analyses of mechanical stress-induced factors revealed that the expression of mechano-growth factor (MGF), systemic insulin-like growth factor I, and the mechanotransduction protein, Yes-associated protein 1 (YAP1), was decreased in untreated immobilized soleus muscle, whereas vibration stimulation restored their expression. No change in the level of phosphorylation of YAP1Ser127 was observed, leading to no change in p-YAP1/YAP1 ratio in vibration-treated immobilized soleus muscle. The results indicate that vibration stimulus is effective to restore immobilization-induced inactivation of YAP1 pathway. Phosphorylation of ERK 1/2, but not AKT, was enhanced in vibration-treated immobilized soleus muscle. Furthermore, vibration stimuli restored immobilization-induced downregulation of the paired box transcription factor, PAX7, a critical factor for regenerative myogenesis in muscle satellite cells. Our results indicate that cyclic vibration stimuli are effective in activating satellite cells and facilitate recovery from immobilization-induced oxidative myofiber atrophy through upregulation of MGF and YAP1.

(Pro)renin receptor accelerates development of sarcopenia via activation of Wnt/YAP signaling axis.

To extend life expectancy and ensure healthy aging, it is crucial to prevent and minimize age-induced skeletal muscle atrophy, also known as sarcopenia. However, the disease's molecular mechanism remains unclear. The age-related Wnt/ß-catenin signaling pathway has been recently shown to be activated by the (pro)renin receptor ((P)RR). We report here that (P)RR expression was increased in the atrophied skeletal muscles of aged mice and humans. Therefore, we developed a gain-of-function model of age-related sarcopenia via transgenic expression of (P)RR under control of the CAG promoter. Consistent with our hypothesis, (P)RR-Tg mice died early and exhibited muscle atrophy with histological features of sarcopenia. Moreover, Wnt/ß-catenin signaling was activated and the regenerative capacity of muscle progenitor cells after cardiotoxin injury was impaired due to cell fusion failure in (P)RR-Tg mice. In vitro forced expression of (P)RR protein in C2C12 myoblast cells suppressed myotube formation by activating Wnt/ß-catenin signaling. Administration of Dickkopf-related protein 1, an inhibitor of Wnt/ß-catenin signaling, and anti-(P)RR neutralizing antibody, which inhibits binding of (P)RR to the Wnt receptor, significantly improved sarcopenia in (P)RR-Tg mice. Furthermore, the use of anti-(P)RR neutralizing antibodies significantly improved the regenerative ability of skeletal muscle in aged mice. Finally, we show that Yes-associated protein (YAP) signaling, which is coordinately regulated by Wnt/ß-catenin, contributed to the development of (P)RR-induced sarcopenia. The present study demonstrates the use of (P)RR-Tg mice as a novel sarcopenia model, and shows that (P)RR-Wnt-YAP signaling plays a pivotal role in the pathogenesis of this disease.

The updated retrospective questionnaire study of sporadic inclusion body myositis in Japan.

BACKGROUND: Sporadic inclusion body myositis (sIBM) is the most prevalent muscle disease in elderly people, affecting the daily activities. sIBM is progressive with unknown cause and without effective treatment. In 2015, sIBM was classified as an intractable disease by the Japanese government, and the treatment cost was partly covered by the government. This study aimed to examine the changes in the number of patients with sIBM over the last 10 years and to elucidate the cross-sectional profile of Japanese patients with sIBM. METHODS: The number of sIBM patients was estimated through a reply-paid postcard questionnaire for attending physicians. Only patients diagnosed as "definite" or "probable" sIBM by clinical and biopsy sIBM criteria were included in this study (Lancet Neurol 6:620-631, 2007, Neuromuscul Disord 23:1044-1055, 2013). Additionally, a registered self-administered questionnaire was also sent to 106 patients who agreed to reply via their attending physician, between November 2016 and March 2017. RESULTS: The number of patients diagnosed with sIBM for each 5-year period was 286 and 384 in 2011 and 2016, respectively. Inability to stand-up, cane-dependent gait, inability to open a plastic bottle, choking on food ingestion, and being wheelchair-bound should be included as sIBM milestones. Eight patients were positive for anti-hepatitis C virus antibody; three of them were administered interferon before sIBM onset. Steroids were administered to 33 patients (31.1%) and intravenous immunoglobulin to 46 patients (43.4%). From 2016 to 2017, total of 70 patients applied for the designated incurable disease medical expenses subsidy program. Although the treatment cost was partly covered by the government, many patients expressed psychological/mental and financial anxieties. CONCLUSIONS: We determined the cross-sectional profile of Japanese patients with sIBM. Continuous support and prospective surveys are warranted.

Dropped Head Syndrome and the Presence of Rimmed Vacuoles in a Muscle Biopsy in Scleroderma-polymyositis Overlap Syndrome Associated with Anti-Ku Antibody.

A 66-year-old woman with a history of interstitial lung disease presented with a 3-month history of dropped head syndrome (DHS), followed by camptocormia and extremity weakness. A clinical examination revealed Raynaud phenomenon, arthralgia, distal skin sclerosis, and microbleeds in the nailfold capillaries. An anti-Ku antibody test was positive. A muscle biopsy revealed inflammatory myopathy with rimmed vacuoles (RVs). The diagnosis of scleroderma-polymyositis (SSc-PM) overlap syndrome was made. RVs on a muscle biopsy in a patient with inflammatory myositis involving axial muscles may be seen either in inclusion body myositis or SSc-PM overlap syndrome. The examination of the skin and autoantibody testing help determine the diagnosis and treatment strategy.

Influenza A (H3N2)-induced rhabdomyolysis complicating anterior compartment syndrome: Serial changes in muscle MRI T2 fat suppression imaging.

BACKGROUND: Rhabdomyolysis with influenza infection is rarely reported in adults. We report here influenza A induced rhabdomyolysis and anterior compartment syndrome (ACS). CASE REPORT: This case report describes a 43-year-old woman exhibiting influenza A induced rhabdomyolysis. High levels of creatine kinase (97,000 IU/L) and high titer of anti-influenza A virus antibody (H3N2) (320 ×) with negative anti-influenza B virus antibody were observed. T2 fat suppression muscle MRI imaging showed high-intensity signals in rectus femoris, vastus lateralis, adductor magnus, and semimembranosus (SM) muscles. The existence of ACS was suspected out. Muscle biopsy showed that fiber size variations exist without infiltration of inflammatory cells. The symptoms and muscle MRI findings of T2 fat suppression imaging was markedly improved. CONCLUSIONS: Muscle MRI T2 fat suppression imaging is a useful method to monitor influenza A induced rhabdomyolysis. We should keep in mind the possibilities of rhabdomyolysis and ACS in patients with influenza A infection presenting serious muscle pain.

Profile of cognitive function in adults with duchenne muscular dystrophy.

BACKGROUND: Several studies have examined intellectual functioning of boys with duchenne muscular dystrophy (DMD). However, little is known about the remaining cognitive weaknesses in adults with DMD. OBJECTIVE: The purpose of this study was to investigate the profile of cognitive functioning that is characteristics of adults with DMD. METHODS: Twenty-four subscales from the Wechsler Adult Intelligence Scale III (WAIS-III), the Clinical Assessment for Attention (CAT), and the Wechsler Memory Scale Revised (WMS-R) were used to assess participants with DMD (N=15; mean age=30.4years). RESULTS: Scores for Picture Completion, Arithmetic, Matrix Reasoning, Symbol Search, Letter-Number Sequencing, and Digit Span of the WAIS-III; all CAT scores, and Logical Memory and Delayed Logical Memory from the WMS-R were significantly deficient in adults with DMD in comparison to the normal population. CONCLUSION: The ability to sequentially process auditory and visual information remains impaired in adults with DMD.

Multicenter questionnaire survey for sporadic inclusion body myositis in Japan.

BACKGROUND: Sporadic inclusion body myositis (sIBM) is the most prevalent acquired muscle disease in the elderly. sIBM is an intractable and progressive disease of unknown cause and without effective treatment. The etiology of sIBM is still unknown; however, genetic factors, aging, lifestyles, and environmental factors may be involved. The purpose of this study is to elucidate the cross-sectional profile of patients affected by sIBM in Japan. METHODS: We surveyed patient data for 146 cases diagnosed at a number of centers across Japan. We also issued a questionnaire for 67 patients and direct caregivers to further elucidate the natural history of the disease. RESULTS: The mean age at the onset was 63.4 ± 9.2 years. The mean length of time from the onset to diagnosis was 55.52 ± 49.72 months, suggesting that there is a difficulty in diagnosing this disease with long-term consequences because of late treatment. 73 % described the psychological/mental aspect of the disease. The most popular primary caregiver was the patient's spouse and 57 % patients mentioned that they were having problems managing the finances. CONCLUSIONS: Through these surveys, we described the cross-sectional profiles of sIBM in Japan. Many patients described psychological/mental and financial anxiety because of the aged profile of sIBM patients. The profiles of sIBM patients are similar to those in Western countries.

Muscle MRI of the Upper Extremity in the Myotonic Dystrophy Type 1.

BACKGROUND: The purpose of this study was to explore the relation between muscle MRI findings and weakness of the upper extremity muscles in patients with myotonic dystrophy type 1 (DM1). METHODS: Nineteen DM1 patients from 15 families were enrolled in this study. Muscle weakness was evaluated using the modified Medical Research Council scale. Subjects also underwent a genetic study and muscle MRI of the upper extremities. RESULTS: In patients with DM1, the flexor digitorum profundus (FDP), flexor pollicis longus, flexor digitorum superficialis (FDS), extensor pollicis, abductor pollicis longus (APL), lateral head of triceps brachii and infraspinatus (INF) muscles were frequently and severely affected. Muscle strength was significantly correlated with the severity of muscle MRI findings in the FDP, short head of biceps brachii (SBB), and medial head of triceps brachii muscles. Disease duration was correlated significantly with MRI findings in the FDP, FDS, long head of biceps brachii, INF, APL, and SBB muscles. Unexpectedly, the degree of trinucleotide expansion of myotonin protein kinase was not correlated with muscle MRI findings. CONCLUSION: Muscle MRI of the upper extremity is useful to detect affected muscles in DM1 patients.

Clinical and Electron Microscopic Findings in Two Patients with Mitochondrial Myopathy Associated with Episodic Hyper-creatine Kinase-emia.

Mitochondrial myopathy with episodic hyper-creatine kinase (CK)-emia (MIMECK) is a new disease entity characterized by episodic or persistent muscle weakness and elevated CK levels. We herein report two cases of MIMECK with the findings of histopathological studies. Histopathological examinations revealed strongly succinate dehydrogenase-reactive vessels. Electron microscopy showed abnormal mitochondria in the vessels and proliferating and vacuolated mitochondria under the sarcolemma. Both patients exhibited recurrent severe myalgia, weakness and increased CK levels. L-arginine treatment significantly ameliorated their muscle symptoms. These findings indicate that mitochondrial angiopathy plays an important role in the pathophysiology of MIMECK. L-arginine may be a potential therapeutic agent for this disorder.

New type of encephalomyelitis responsive to trimethoprim/sulfamethoxazole treatment in Japan.

OBJECTIVE: To determine the causative pathogen and investigate the effective treatment of a new type of encephalomyelitis with an unknown pathogen in Japan and report the preliminary ultrastructural and genomic characterization of the causative agent. METHODS: From 2005 to 2012, we treated 4 Japanese patients with geographic clustering and comparable clinical features, serum/CSF cytology, and radiologic findings. Brain biopsy was conducted in all patients to analyze neuropathologic changes by histology, and electron microscopy was applied to reveal the features of the putative pathogen. Genomic DNA was obtained from the affected brain tissues and CSF, and an unbiased high-throughput sequencing approach was used to screen for specific genomic sequences indicative of the pathogen origin. RESULTS: All patients exhibited progressive dementia with involuntary tongue movements. Cytologic examination of CSF revealed elevated mononuclear cells. Abnormal MRI signals were observed in temporal lobes, subcortical white matter, and spinal cord. Biopsied brain tissue exhibited aggregated periodic acid-Schiff-positive macrophages and 2-7 µm diameter round/oval bodies without nuclei or cell walls scattered around the vessels. Unbiased high-throughput sequencing identified more than 100 archaea-specific DNA fragments. All patients were responsive to trimethoprim/sulfamethoxazole (TMP-SMX) plus corticosteroid therapy. CONCLUSIONS: We report 4 cases of encephalomyelitis due to an unknown pathogen. On the basis of ultrastructural and genomic studies, we propose a new disease entity resulting from a causative pathogen having archaeal features. TMP-SMX therapy was effective against this new type of encephalomyelitis.

Myopathy in a patient with systemic AA amyloidosis possibly induced by psoriasis vulgaris: An autopsy case.

INTRODUCTION: Amyloid myopathy is a rare manifestation of primary systemic amyloid light-chain (AL) amyloidosis, but it has not been reported to occur in secondary amyloid A (AA) amyloidosis. METHODS: We describe a 46-year-old man with psoriasis vulgaris who presented with idiopathic upper and lower limb weakness and was eventually diagnosed with hypertrophic cardiomyopathy. Muscle biopsy findings were compatible with mild inflammatory myopathy. He died of cardiopulmonary arrest, and an autopsy was performed. RESULTS: The autopsy revealed amyloid plaques immunopositive for AA (but not AL or transthyretin) in the perimysial, perivascular, and endomysial regions of the iliopsoas muscle. The final diagnosis was systemic AA amyloidosis with muscle amyloid angiopathy, possibly induced by psoriasis vulgaris. CONCLUSION: This is an extremely rare autopsy case of myopathy in a patient with systemic AA amyloidosis. The reason for the unusually large amount of amyloid deposition in muscle blood vessel walls remains unclear.

Clinical presentation of axial myopathy in two siblings with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP).

BACKGROUND: The clinical features of myositis related with Human T-cell leukemia virus type 1 (HTLV-1) remains unclear despite epidemiological studies suggesting inflammatory myopathy associated with the virus. CASE PRESENTATION: Here, we described the clinical presentations, muscle biopsy studies and laboratory results of two siblings with HTLV-1-associated myelopathy / tropical spastic paraparesis (HAM/TSP) who were affected with lumbar lordosis. Computed tomography (CT) scans demonstrated marked paraspinal muscle atrophy in both patients. Immunohistochemical studies of biopsy tissue obtained from one of the patients revealed inflammatory change of the muscle. Upon oral prednisolone therapy, the patient showed improvement in muscle strength and serum creatine kinase (CK) level. CONCLUSION: Myopathy or specifically axial myopathy should be considered as clinical symptom when treating the patients with HTLV-1 infection.

The E3 ligase synoviolin controls body weight and mitochondrial biogenesis through negative regulation of PGC-1ß.

Obesity is a major global public health problem, and understanding its pathogenesis is critical for identifying a cure. In this study, a gene knockout strategy was used in post-neonatal mice to delete synoviolin (Syvn)1/Hrd1/Der3, an ER-resident E3 ubiquitin ligase with known roles in homeostasis maintenance. Syvn1 deficiency resulted in weight loss and lower accumulation of white adipose tissue in otherwise wild-type animals as well as in genetically obese (ob/ob and db/db) and adipose tissue-specific knockout mice as compared to control animals. SYVN1 interacted with and ubiquitinated the thermogenic coactivator peroxisome proliferator-activated receptor coactivator (PGC)-1ß, and Syvn1 mutants showed upregulation of PGC-1ß target genes and increase in mitochondrion number, respiration, and basal energy expenditure in adipose tissue relative to control animals. Moreover, the selective SYVN1 inhibitor LS-102 abolished the negative regulation of PGC-1ß by SYVN1 and prevented weight gain in mice. Thus, SYVN1 is a novel post-translational regulator of PGC-1ß and a potential therapeutic target in obesity treatment.

Partial deficiency of emerin caused by a splice site mutation in EMD.

Emery-Dreifuss muscular dystrophy (EDMD) is caused by mutations in the EMD gene on the X chromosome, which codes for emerin, an inner nuclear membrane protein. Monoclonal antibodies against the N-terminus of emerin protein are used to screen for emerin deficiency in clinical practice. However, these tests may not accurately reflect the disease in some cases. We herein describe the identification of a splice site mutation in the EMD gene in a Japanese patient who suffered from complete atrioventricular conduction block, mild muscle weakness and joint contracture, and a persistently elevated serum creatine kinase level. We used multiple antibodies to confirm the presence of a novel truncating mutation in emerin without the transmembrane region and C-terminus in the skeletal muscle.

Effect of isolated AMP deaminase deficiency on skeletal muscle function.

Mutation of the AMP deaminase 1 (AMPD1) gene, the predominate AMPD gene expressed in skeletal muscle, is one of the most common inherited defects in the Caucasian population; 2-3% of individuals in this ethnic group are homozygous for defects in the AMPD1 gene. Several studies of human subjects have reported variable results with some studies suggesting this gene defect may cause symptoms of a metabolic myopathy and/or easy fatigability while others indicate individuals with this inherited defect are completely asymptomatic. Because of confounding problems in assessing muscle symptoms and performance in human subjects with different genetic backgrounds and different environmental experiences such as prior exercise conditioning and diet, a strain of inbred mice with selective disruption of the AMPD1 was developed to study the consequences of muscle AMPD deficiency in isolation. Studies reported here demonstrate that these animals are a good metabolic phenocopy of human AMPD1 deficiency but they exhibit no abnormalities in muscle performance in three different exercise protocols.

Inhibition of SMG-8, a subunit of SMG-1 kinase, ameliorates nonsense-mediated mRNA decay-exacerbated mutant phenotypes without cytotoxicity.

Nonsense-mediated mRNA decay (NMD) is an mRNA surveillance mechanism that eliminates aberrant mRNAs containing premature termination codons (PTCs). NMD inhibits the production of aberrant proteins that still retain, at least in part, wild-type function as well as dominant-negative peptides. Therefore, the selective inhibition of NMD has the potential to ameliorate NMD-exacerbated mutant phenotypes. However, we do not have sufficient knowledge of how to effectively suppress NMD with minimum cytotoxic effects. In this study, we aimed to identify NMD-related factors that can be targeted to efficiently inhibit NMD without causing significant cytotoxicity to restore the levels of truncated but partially functional proteins. We evaluated the knockdown of 15 NMD components in Ullrich congenital muscular dystrophy fibroblasts, which have a homozygous frameshift mutation causing a PTC in the collagen type VI α 2 gene. Of the 15 NMD factors tested, knockdown of SMG-8 produced the best effect for restoring defective mRNA and protein levels without affecting cell growth, cell-cycle progression, or endoplasmic reticulum stress. The efficacy of SMG-8 knockdown to improve the mutant phenotype was confirmed using another cell line, from a cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy patient who carries a PTC-containing mutation in HtrA serine peptidase 1. Our results suggest that SMG-8 is an appropriate target for inhibiting NMD to improve NMD-exacerbated mutant phenotypes. NMD inhibition by knockdown of SMG-8 may also be useful to induce synergy in combining the use of read-through drugs for patients with nonsense mutation-associated diseases.