Age-related bone loss is associated with changes in bone cellularity with characteristically low levels of osteoblastogenesis. The mechanisms that explain these changes remain unclear. Although recent in vitro evidence has suggested a new role for proteins of the nuclear envelope in osteoblastogenesis, the role of these proteins in bone cells differentiation and bone metabolism in vivo remains unknown. In this study, we used the lamin A/C null (Lmna −/−) mice to identify the role of lamin A/C in bone turnover and bone structure in vivo. At three weeks of age, histological and micro computed tomography measurements of femurs in Lmna −/− mice revealed a significant decrease in bone mass and microarchitecture in Lmna −/− mice as compared with their wild type littermates. Furthermore, quantification of cell numbers after normalization with bone surface revealed a significant reduction in osteoblast and osteocyte numbers in Lmna −/− mice compared with their WT littermates. In addition, Lmna −/− mice have significantly lower osteoclast number, which show aberrant changes in their shape and size. Finally, mechanistic analysis demonstrated that absence of lamin A/C is associated with increase expression of MAN-1 a protein of the nuclear envelope closely regulated by lamin A/C, which also colocalizes with Runx2 thus affecting its capacity as osteogenic transcription factor. In summary, these data clearly indicate that the presence of lamin A/C is necessary for normal bone turnover in vivo and that absence of lamin A/C induces low bone turnover osteopenia resembling the cellular changes of age-related bone loss.

Rationale: Mutations in the LMNA gene, which encodes the nuclear lamina proteins lamin A and lamin C, are the most common cause of familial dilated cardiomyopathy (DCM). Mechanical stress-induced apoptosis has been proposed as the mechanism underpinning DCM in lamin A/C-deficient hearts, but supporting in vivo evidence has been lacking. Objective: Our aim was to study interventions to modify mechanical stress in heterozygous Lmna knockout (Lmna ؉/؊ ) mice. Methods and Results: Cardiac structure and function were evaluated before and after exercise training, thoracic aortic constriction, and carvedilol treatment. Lmna ؉/؊ mice develop adult-onset DCM with relatively more severe disease in males. Lmna ؉/؊ cardiomyocytes show altered nuclear morphology and perinuclear desmin organization, with enhanced responses to hypo-osmotic stress indicative of cytoskeletal instability. Despite these structural defects that provide a template for mechanical stress-induced damage, young Lmna ؉/؊ mice subjected to 6 weeks of moderate or strenuous exercise training did not show induction of apoptosis or accelerated DCM. In contrast, regular moderate exercise attenuated DCM development in male Lmna ؉/؊ mice. Sustained pressure overload generated by thoracic aortic constriction depressed ventricular contraction in young wild-type and Lmna ؉/؊ mice with no sex or genotype differences in the time-course or severity of response. Treatment of male Lmna ؉/؊ mice from 12 to 40 weeks with the ␤-blocker, carvedilol, prevented the dilatation and contractile dysfunction that was observed in placebo-treated mice. Conclusions: These data suggest that factors other than mechanical stress-induced apoptosis contribute to DCM and provide the first demonstration that regular moderate exercise and carvedilol can modify disease progression in lamin A/C-deficient hearts. (Circ Res. 2010;106:573-582.)Key Words: familial dilated cardiomyopathy Ⅲ lamin A/C Ⅲ mechanical stress Ⅲ exercise Ⅲ carvedilol M utations in the LMNA gene that encodes the nuclear lamina proteins lamin A and lamin C are the most common cause of familial dilated cardiomyopathy (DCM) identified to date, 1 accounting for 5% to 10% familial DCM overall and 30% to 45% families with DCM and conduction system disease (CD). [2][3][4][5] Affected individuals frequently have a rapidly progressive downhill clinical course, requiring pacemaker implantation or heart transplantation, with an increased risk of sudden death. [2][3][4][5] Despite the clinical importance of LMNA mutations, very little is known about mechanisms of disease pathogenesis and strategies to prevent DCM have not been investigated.Because one-third of DCM-causing LMNA mutations are stop codons, splice site variants or insertions/deletions that reduce lamin A/C protein levels, 1,5 Lmna knockout mice are a useful and clinically relevant model to study DCM mechanisms. 6 We have previously reported that homozygous Lmna knockout (Lmna Ϫ/Ϫ ) mice exhibit severe DCM by 4 to 6 weeks. 7 Heterozygous Lmna knockout (Lmna ϩ/Ϫ ) mice show ...

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The re-emergence of Chikungunya virus (CHIKV), an Alphavirus that causes debilitating fever, nausea, headache and polyarthralgia in humans, is responsible for major disease outbreaks in many regions and rekindled interest in studying the pathophysiology of CHIKV infection. There is currently no effective antiviral or vaccine against this disease. Mouse models of CHIKV infection have been developed to investigate CHIKV pathogenesis; however, each model presents both advantages and disadvantages. Nevertheless, in vivo studies have provided us with invaluable information to help understand the mechanism of CHIKV infections and enable the testing of novel therapeutic interventions."The lack of appropriate models that accurately replicate human disease and physiology has no doubt contributed to the high failure rate (50%) of investigational new drugs in Phase II clinical trials."CHIKV is a positive-sense ssRNA virus, belonging to the family of Togaviridae, genus Alphavirus. It was first isolated in Tanzania, Africa in 1952 [1] and mainly transmitted by Aedes mosquitoes, Aedes aegypti and Aedes albo pictus [2,3]. CHIKV can cause diseases in human characterized by fever, nausea, rash, headache, myalgia and acute/persistent polyarthralgia [4,5]. In rare cases, neurological complications can be observed in neonates as well as in adults [6,7]. In recent years, the re-emergence of CHIKV has led to major outbreaks in many regions [8,9], which can result in increasing social and economic burdens. Currently, there are no known vaccines or specific treatment regimens available for CHIKV infection [10].Ideally, to obtain a more precise understanding of host-virus interaction and disease pathophysiology, clinical research studies in CHIKVinfected patients are recommended. However, research studies in humans are hampered by ethical issues and difficulties in acquiring human tissues for downstream investigation. To overcome this limitation, mouse models of CHIKV infection developed to gain further insights into CHIKV disease pathogenesis and evaluate potential novel antiviral interventions. A major advantage of using mouse models is the ability to obtain tissue samples at various time-points postinfection (pi) from different mice of the same genetic background to better understand the pathogenesis of CHIKV.Mice of different genetic backgrounds and ages were used by various research groups to generate mouse models of CHIKV infection. Most of the models exhibited CHIKV tropism in muscles and joints similar to those observed in humans. A study by Couderc et al. demonstrated that 6-dayold and 9-day-old wild-type (WT) C57BL6/J mice, when infected intradermally (id.) in the ventral thorax, showed muscle weakness leading to paralysis from day 6 pi. Only 50% of the 9-day-old infected mice survived, while all 6-dayold infected mice died by day 12 pi. From day 3 pi, low levels of infectious CHIKV were found in the blood, spleen, liver and brain, and higher levels of virus were observed in the skin, joints and muscle [11]. A second investigat...

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