SUMMARY Wnt signaling plays critical roles in development of various organs and pathogenesis of many diseases, and augmented Wnt signaling has recently been implicated in mammalian aging and aging-related phenotypes. We here report that complement C1q activates canonical Wnt signaling and promotes aging-associated decline in tissue regeneration. Serum C1q concentration is increased with aging, and Wnt signaling activity is augmented during aging in the serum and in multiple tissues of wild-type mice, but not in those of C1qa-deficient mice. C1q activates canonical Wnt signaling by binding to Frizzled receptors and subsequently inducing C1s-dependent cleavage of the ectodomain of Wnt coreceptor low-density lipoprotein receptor-related protein 6. Skeletal muscle regeneration in young mice is inhibited by exogenous C1q treatment, whereas aging-associated impairment of muscle regeneration is restored by C1s inhibition or C1qa gene disruption. Our findings therefore suggest the unexpected role of complement C1q in Wnt signal transduction and modulation of mammalian aging.

The DNA damage response (DDR) plays a pivotal role in maintaining genome integrity. DNA damage and DDR activation are observed in the failing heart, however, the type of DNA damage and its role in the pathogenesis of heart failure remain elusive. Here we show the critical role of DNA single-strand break (SSB) in the pathogenesis of pressure overload-induced heart failure. Accumulation of unrepaired SSB is observed in cardiomyocytes of the failing heart. Unrepaired SSB activates DDR and increases the expression of inflammatory cytokines through NF-κB signalling. Pressure overload-induced heart failure is more severe in the mice lacking XRCC1, an essential protein for SSB repair, which is rescued by blocking DDR activation through genetic deletion of ATM, suggesting the causative role of SSB accumulation and DDR activation in the pathogenesis of heart failure. Prevention of SSB accumulation or persistent DDR activation may become a new therapeutic strategy against heart failure.

Hypertension induces structural remodelling of arteries, which leads to arteriosclerosis and end-organ damage. Hyperplasia of vascular smooth muscle cells (VSMCs) and infiltration of immune cells are the hallmark of hypertensive arterial remodelling. However, the precise molecular mechanisms of arterial remodelling remain elusive. We have recently reported that complement C1q activates β-catenin signalling independent of Wnts. Here, we show a critical role of complement C1-induced activation of β-catenin signalling in hypertensive arterial remodelling. Activation of β-catenin and proliferation of VSMCs were observed after blood-pressure elevation, which were prevented by genetic and chemical inhibition of β-catenin signalling. Macrophage depletion and C1qa gene deletion attenuated the hypertension-induced β-catenin signalling, proliferation of VSMCs and pathological arterial remodelling. Our findings unveil the link between complement C1 and arterial remodelling and suggest that C1-induced activation of β-catenin signalling becomes a novel therapeutic target to prevent arteriosclerosis in patients with hypertension.

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SummaryDuchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene which encodes dystrophin protein.Dystrophin defect affects cardiac muscle as well as skeletal muscle. Cardiac dysfunction is observed in all patients with DMD over 18 years of age, but there is no curative treatment for DMD cardiomyopathy. To establish novel experimental platforms which reproduce the cardiac phenotype of DMD patients, here we established iPS cell lines from T lymphocytes donated from two DMD patients, with a protocol using Sendai virus vectors. We successfully conducted the differentiation of the DMD patient-specific iPS cells into beating cardiomyocytes. DMD patient-specific iPS cells and iPS cell-derived cardiomyocytes would be a useful in vitro experimental system with which to investigate DMD cardiomyopathy. ( DMD is caused by mutations in the DMD gene which encodes dystrophin protein. Dystrophin protein constitutes a core element of dystrophin-glycoprotein complex, and plays essential roles in transmitting force and maintaining sarcolemma stability. Lack of dystrophin protein impairs membrane integrity and causes progressive degeneration and loss of skeletal muscle. Dystrophin defect also affects cardiac muscle and cardiac dysfunction is observed in all patients with DMD over 18 years of age.2) With recent advances in the management of respiratory failure for patients with DMD, increasing attention has been paid to cardiac dysfunction since the heart failure is becoming the most frequent cause of death among adult DMD patients.3) Although medical treatments using betablockers and angiotensin converting enzyme inhibitors have been reported to delay progression of DMD cardiomyopathy, 4-6) the effects are limited. Exon skipping has been developed as a novel gene therapy for DMD and some effects have been observed in skeletal muscles, however, the recovery of dystrophin was only scarcely observed in heart muscle due to the difficulty of delivering antisense oligonucleotides to cardiomyocytes.7) Thus, we need to clarify the underlying mechanisms of DMD-associated cardiomyopathy and develop novel therapeutic strategies.To date, mdx mice have been widely used as an animal model of dystrophin gene abnormality. Recent studies have reported various abnormalities in cardiomyocytes of mdx mice such as increased susceptibility to stretch-mediated calcium overload, 8) abnormal activation in stretch-activated channels, 9) diastolic calcium leak from sarcoplasmic reticulum, 10,11) and hyperactivation of X-ROS signaling.12) Nevertheless, mdx mice have critical limitations as a model for DMD cardiomyopathy since they do not develop heart failure. 13,14) On the other hand, using both in vitro and in vivo non-genetic rat models, a recent study demonstrated that microRNA-340-5p may be involved in the progression of heart failure through the interaction with DMD gene.15) Considering these issues, novel experimental platforms that reproduce the cardiac phenotype of DMD patients is critically required for the development of new drugs a...