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.

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.

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.

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.

Muscle wasting associated with pathologic change is a risk factor for the exacerbation of joint swelling in collagen-induced arthritis in cynomolgus monkeys.

BACKGROUND: Not only joint destruction but also muscle wasting due to rheumatoid cachexia has been problem in terms of quality of life of patients with rheumatoid arthritis (RA). In the present study, we performed histopathological examination and assessed relationships between characteristic parameters relating to muscle and joint swelling in a collagen-induced arthritis (CIA) model using cynomolgus monkeys (CMs). METHODS: Female CMs were used and CIA was induced by twice immunizations using bovine type II collagen with Freund's complete adjuvant. Arthritis level was evaluated from the degree of swelling at the peripheral joints of the fore and hind limbs. Food consumption, body weight, and serum biochemical parameters were measured sequentially. Five or 6 animals per time point were sacrificed at 2, 3, 5 and 9 weeks after the first immunization to obtain quadriceps femoris specimens for histopathology. Pimonidazole hydrochloride was intravenously administered to determine tissue hypoxia in skeletal muscle. RESULTS: Gradual joint swelling was observed and the maximum arthritis score was noted at Week 5. In histopathology, necrosis of muscle fiber in the quadriceps femoris was observed only at Week 2 and the most significant findings such as degeneration, atrophy, and regeneration of muscle fiber were mainly observed at Week 5. Food consumption was decreased up to Week 4 but recovered thereafter. Body weight decreased up to Week 5 and did not completely recover thereafter. A biphasic increase in serum cortisol was also observed at Weeks 2 and 5. Histopathology showed that muscle lesions were mainly composed of degeneration and atrophy of the muscle fibers, and ATPase staining revealed that the changes were more pronounced in type II muscle fiber than type I muscle fiber. In the pimonidazole experiment, mosaic pattern in skeletal muscle was demonstrated in the intact animal, but not the CIA animal. Increased arthritis score was accompanied by a decrease in serum creatinine, a marker that reflects muscle mass. CONCLUSIONS: Muscle wasting might exacerbate joint swelling in a collagen-induced arthritis model of cynomolgus monkeys.

A new mitochondria-related disease showing myopathy with episodic hyper-creatine kinase-emia.

OBJECTIVE: To elucidate the relationship between mitochondrial DNA (mtDNA) alterations and a mitochondrial disease with a distinct combination of characteristic symptoms, namely episodic hyper-creatine kinase (CK)-emia and mild myopathy. METHODS: We selected 9 patients with mtDNA np8291 alteration from 586 patients suspected to have a mitochondrial disease, and assessed them clinically, pathologically, and genetically. These 9 patients had undiagnosed mitochondrial myopathy with episodic hyper-CK-emia, all showing similar symptoms and progression. RESULTS: Patients had mild muscle weakness and episodic hyper-CK-emia triggered by infections or drugs. Five of 9 patients were initially diagnosed with other conditions, such as myasthenia gravis, polymyositis, viral myositis, and drug-induced myopathy, because these conditions were acute or subacute, and 9 patients showed the same 16 mtDNA alterations, which have been reported to be nonpathological polymorphisms. Muscle biopsy revealed ragged-red fibers, highly expressed succinate dehydrogenase staining fibers, and cytochrome c oxidase-deficient fibers. Because their mitochondrial sequence data was almost the same, and 9 patients live in widely separated cities in Japan, the alterations may have arisen from a single source. INTERPRETATION: These findings suggest that mild myopathy with episodic hyper-CK-emia associated with some of the 16 mtDNA alterations or at least with their mitochondria, could be a novel mitochondrial disease. Therefore, we propose that this disease be named as "mitochondrial myopathy with episodic hyper-CK-emia (MIMECK)." These alterations could work concomitantly and probably modify the impact of medications or other environmental factors. We believe these findings provide an insight into a novel aspect of mitochondrial disease pathogenesis.

A new phenotype of mitochondrial disease characterized by familial late-onset predominant axial myopathy and encephalopathy.

Axial myopathy is a rare neuromuscular disease that is characterized by paraspinal muscle atrophy and abnormal posture, most notably camptocormia (also known as bent spine). The genetic cause of familial axial myopathy is unknown. Described here are the clinical features and cause of late-onset predominant axial myopathy and encephalopathy. A 73-year-old woman presented with a 10-year history of severe paraspinal muscle atrophy and cerebellar ataxia. Her 84-year-old sister also developed late-onset paraspinal muscle atrophy and generalized seizures with encephalopathy. Computed tomography showed severe atrophy and fatty degeneration of their paraspinal muscles. Their mother and maternal aunt also developed bent spines. The existence of many ragged-red fibers and cytochrome c oxidase-negative fibers in the biceps brachii muscle of the proband indicated a mitochondrial abnormality. No significant abnormalities were observed in the respiratory chain enzyme activities; however, the activities of complexes I and IV were relatively low compared with the activities of other complexes. Sequence analysis of the mitochondrial DNA from the muscle revealed a novel heteroplasmic mutation (m.602C>T) in the mitochondrial tRNA(Phe) gene. This familial case of late-onset predominant axial myopathy and encephalopathy may represent a new clinical phenotype of a mitochondrial disease.

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.

Inclusion body myositis associated with human T-lymphotropic virus-type I infection: eleven patients from an endemic area in Japan.

The objective of this study was to investigate the association of human T-lymphotropic virus-type I (HTLV-I) infection with sporadic inclusion body myositis in 11 patients from an endemic area in Japan. The clinical features were consistent with sporadic inclusion body myositis, and anti-HTLV-I antibodies were present in the sera of all patients. Their muscle biopsies showed the diagnostic features of inclusion body myositis, including endomysial T-cell infiltration, rimmed vacuoles, deposits of phosphorylated tau, and abnormal filaments in the nuclei and cytoplasm of the myofibers. The fibers expressed major histocompatibility complex class I antigens and were invaded by CD8 and CD4 cells. In a single human leukocyte antigen-A2-positive patient, in situ human leukocyte antigen-A*0201 / Tax11-19-pentamer staining showed pentamer-positive cells surrounding the muscle fibers. Double-immunogold silver staining and polymerase chain reaction in situ hybridization revealed that HTLV-I proviral DNA was localized on helper-inducer T cells, but not on muscle fibers. Human T-lymphotropic virus-type I proviral loads in peripheral blood mononuclear cells from each patient were similar to those in HTLV-I-associated myelopathy/tropical spastic paraparesis. This study suggests that HTLV-I infection may be one of the causes of sporadic inclusion body myositis, as has been reported in human immunodeficiency virus type-1 infection.

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.

Different pattern of HSP47 expression in skeletal muscle of patients with neuromuscular diseases.

Heat shock protein (HSP) 47, a collagen-specific molecular chaperone, is involved in the processing and secretion of procollagens, and its expression is increased in various fibrotic diseases. However, its involvement in muscle diseases is unknown. In this study, we analyzed HSP47 expression in muscular dystrophies and other muscle diseases. We found an overexpression of HSP47 in fibrous connective tissue and in the adjacent muscle membrane in various muscular dystrophies. However, in Ullrich congenital muscular dystrophy (UCMD), the overexpression of HSP47 was found only in the connective tissue, and not in the muscle membrane. The overexpression of HSP47 was found only in the muscle membrane in the case of active inflammatory myopathy. In particular, HSP47 was strongly expressed in the membrane of regenerating fibers. We found that HSP47 in the muscle membrane locates in the basement membrane with confocal microscopy. Our findings suggest that HSP47 may be involved in the repair or regeneration of muscle fibers in addition to the fibrotic change in the connective tissue.

Targeted deletion of both thymidine phosphorylase and uridine phosphorylase and consequent disorders in mice.

Thymidine phosphorylase (TP) regulates intracellular and plasma thymidine levels. TP deficiency is hypothesized to (i) increase levels of thymidine in plasma, (ii) lead to mitochondrial DNA alterations, and (iii) cause mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). In order to elucidate the physiological roles of TP, we generated mice deficient in the TP gene. Although TP activity in the liver was inhibited in these mice, it was fully maintained in the small intestine. Murine uridine phosphorylase (UP), unlike human UP, cleaves thymidine, as well as uridine. We therefore generated TP-UP double-knockout (TP(-/-) UP(-/-)) mice. TP activities were inhibited in TP(-/-) UP(-/-) mice, and the level of thymidine in the plasma of TP(-/-) UP(-/-) mice was higher than for TP(-/-) mice. Unexpectedly, we could not observe alterations of mitochondrial DNA or pathological changes in the muscles of the TP(-/-) UP(-/-) mice, even when these mice were fed thymidine for 7 months. However, we did find hyperintense lesions on magnetic resonance T(2) maps in the brain and axonal edema by electron microscopic study of the brain in TP(-/-) UP(-/-) mice. These findings suggested that the inhibition of TP activity caused the elevation of pyrimidine levels in plasma and consequent axonal swelling in the brains of mice. Since lesions in the brain do not appear to be due to mitochondrial alterations and pathological changes in the muscle were not found, this model will provide further insights into the causes of MNGIE.

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.

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.