A novel recessive mutation affecting DNAJB6a causes myofibrillar myopathy.

Mutations in the DNAJB6 gene have been identified as rare causes of myofibrillar myopathies. However, the underlying pathophysiologica mechanisms remain elusive. DNAJB6 has two known isoforms, including the nuclear isoform DNAJB6a and the cytoplasmic isoform DNAJB6b, which was thought to be the pathogenic isoform. Here, we report a novel recessive mutation c.695_699del (p. Val 232 Gly fs*7) in the DNAJB6 gene, associated with an apparently recessively inherited late onset distal myofibrillar myopathy in a Chinese family. Notably, the novel mutation localizes to exon 9 and uniquely encodes DNAJB6a. We further identified that this mutation decreases the mRNA and protein levels of DNAJB6a and results in an age-dependent recessive toxic effect on skeletal muscle in knock-in mice. Moreover, the mutant DNAJB6a showed a dose-dependent anti-aggregation effect on polyglutamine-containing proteins in vitro. Taking together, these findings reveal the pathogenic role of DNAJB6a insufficiency in myofibrillar myopathies and expand upon the molecular spectrum of DNAJB6 mutations.

Hypoxia-inducible factor-prolyl hydroxylase inhibitor ameliorates myopathy in a mouse model of chronic kidney disease.

Muscle wasting and diminished physical performance contribute to the morbidity and mortality of chronic kidney disease (CKD), for which no curative therapy exists. Accumulating evidence indicates that impaired angiogenesis occurs in the muscles of CKD models. Therefore, proangiogenesis therapy is considered a potentially effective strategy for limiting CKD-associated myopathy. Hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor (HIF-PHI) stabilizes HIF and enhances muscle angiogenesis during acute ischemia; however, little evidence was available from CKD models. Here, we assessed whether pharmacological activation of HIF by MK-8617 (MK), a novel orally active HIF-PHI, improves CKD-associated myopathy. Mice were divided into sham or CKD groups, and CKD mice were subdivided into CKD + vehicle or MK treatment groups (1.5, 5, or 12.5 mg/kg for 12 wk). In CKD mice, skeletal muscle mass, mitochondrial amount, and exercise capacity decreased compared with sham mice. Compared with the CKD + vehicle group, low (1.5 mg/kg) and medium (5 mg/kg) doses of MK, but not the high dose (12.5 mg/kg), significantly restored these changes and was accompanied by incremental increases in HIF-1α. Furthermore, increased capillary density and area were observed in a MK dose-dependent manner, which is likely related to an improved VEGF response in the skeletal muscle of CKD mice. In addition, macrophage and proinflammatory cytokines, including monocyte chemoattractant protein 1, TNF-α, and IL-6, significantly increased in the high-dose MK group. These results indicate that HIF-PHI provides a potential therapeutic strategy to improve CKD-associated myopathy.

The combination of plasma glutamate and physical impairment after acute stroke as a potential indicator for the early-onset post-stroke depression.

OBJECTS: The present study aimed to investigate the relationship of plasma glutamate levels with the early-onset of post-stroke depression (PSD) and to further explore the prognostic value of plasma glutamate combined with clinical characteristics for the early-onset PSD in the acute ischemic stroke patients. METHODS: Seventy-four patients who admitted to the hospital within 24h of acute ischemic stroke were consecutively recruited and followed up for 2weeks. The Beck Depression Inventory (BDI) and 17-item Hamilton Depression Rating Scale (HAMD-17) were used to screen for depressive symptoms 14days after stroke. Diagnoses of depression were made in accordance with DSM-IV. Plasma glutamate levels were determined by High Performance Liquid Chromatography (HPLC) on days 1 and 14 after stroke for all patients. RESULTS: Plasma glutamate levels were significantly lower in PSD patients than those of non-PSD patients on day 1 after stroke. ROC curve analyses revealed an AUC (area under the ROC curve) of 0.724 (95% CI: 0.584-0.863, p=0.004) and of 0.669 (95% CI: 0.523-0.814, p=0.030) for National Institute of Health Stroke Scale (NIHSS) scores and plasma glutamate levels on day 1 respectively. Combined ROC analyses using the two factors revealed the highest AUC of 0.804 (95% CI: 0.685-0.922, P<0.0001). CONCLUSIONS: These results indicated an association between the early-onset PSD and a low plasma glutamate level following acute ischemic stroke. The combination of reduced plasma glutamate levels and physical impairment (determined by NIHSS) 1day after acute ischemic stroke was a potential diagnostic indicator for early-onset PSD.