New Findings What is the central question of this study?Capillary rarefaction is found in diabetic and aged muscle, whereas exercise increases skeletal muscle angiogenesis. The association implies a crosstalk between muscle cells and endothelial cells. The underlying mechanisms mediating the crosstalk between these cells remains to be elucidated fully. What is the main finding and its importance?Endothelial cell functions are regulated by skeletal muscle cell‐derived exosomes via a vascular endothelial growth factor‐independent pathway. This study reveals a new mechanism mediating the crosstalk between skeletal muscle cells and endothelial cells. Abstract Loss of skeletal muscle capillarization, known as capillary rarefaction, is found in type 2 diabetes, chronic heart failure and healthy ageing and is associated with impaired delivery of substrates to the muscle. However, the interaction and communication of skeletal muscle with endothelial cells in the regulation of capillaries surrounding the muscle remains elusive. Exosomes are a type of secreted extracellular vesicle containing mRNAs, proteins and, especially, microRNAs that exert paracrine and endocrine effects. In this study, we investigated whether skeletal muscle‐derived exosomes (SkM‐Exo) regulate the endothelial cell functions of angiogenesis. We demonstrated that C2C12 myotube‐derived exosomes improved endothelial cell functions, assessed by the proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs), which were increased by 20, 23 and 40%, respectively, after SkM‐Exo exposure. The SkM‐Exo failed to activate HUVEC vascular endothelial growth factor (VEGF) signalling. The SkM‐Exo increased HUVEC reactive oxygen species and activated the nuclear factor‐κB pathway, suggesting that SkM‐Exo‐induced angiogenesis was mediated by a VEGF‐independent pathway. In addition, several angiogenic microRNAs were packaged in SkM‐Exo, with miR‐130a being particularly enriched and successfully transferred from SkM‐Exo to HUVECs. Delivery of miRNAs into endothelial cells might explain the enhancement of reactive oxygen species production and angiogenesis by SkM‐Exo. The potential angiogenic effect of SkM‐Exo could provide an effective therapy for promoting skeletal muscle angiogenesis in diseases characterized by capillary rarefaction or inadequate angiogenesis.
Exercise promotes multiple beneficial effects on muscle function, including induction of mitochondrial biogenesis. miR-133a is a muscle-enriched microRNA that regulates muscle development and function. The role of miR-133a in exercise tolerance has not been fully elucidated. In the current study, mice that were deficient in miR-133a demonstrated low maximal exercise capacity and low resting metabolic rate. Transcription of the mitochondrial biogenesis regulators peroxisome proliferator-activated receptor-γ coactivator 1-α, peroxisome proliferator-activated receptor-γ coactivator 1-β, nuclear respiratory factor-1, and transcription factor A, mitochondrial were lower in miR-133a-deficient muscle, which was consistent with lower mitochondrial mass and impaired exercise capacity. Six weeks of endurance exercise training increased the transcriptional level of miR-133a and stimulated mitochondrial biogenesis in wild-type mice, but failed to improve mitochondrial function in miR-133a-deficient mice. Further mechanistic analysis showed an increase in the miR-133a potential target, IGF-1 receptor, along with hyperactivation of Akt signaling, in miR-133a-deficient mice, which was consistent with lower transcription of the mitochondrial biogenesis regulators. These findings indicate an essential role of miR-133a in skeletal muscle mitochondrial biogenesis, exercise tolerance, and response to exercise training.-Nie, Y., Sato, Y., Wang, C., Yue, F., Kuang, S., Gavin, T. P. Impaired exercise tolerance, mitochondrial biogenesis, and muscle fiber maintenance in miR-133a-deficient mice.
We report a patient with fatal hepatitis B virus (HBV) reactivation after treatment for chronic graft-versus-host disease (GVHD) following allogeneic peripheral blood stem cell transplantation to treat chronic myelogenous leukemia. The presence of antibodies to hepatitis B surface antigen (HBsAb) prior to transplantation indicated previous HBV infection. Liver damage first developed 8 months after transplantation with the disappearance of HBsAb. Hepatitis B antigen was first noted during an examination of liver damage that occurred 22 months after transplantation. Retrospective examination of serum by real-time detection polymerase chain reaction (RTD-PCR) revealed HBV in both the first and second episodes of liver damage (89 copies/mL and 2 x 10(6) copies/mL, respectively). HBV may have been reactivated, leading to fatal liver damage in this HBsAb-positive patient. We propose that RTD-PCR-based analysis should be performed to diagnose liver dysfunction after hematopoietic stem cell transplantation.
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