SummaryAccumulation of adipocytes and collagen type-I-producing cells (fibrosis) is observed in muscular dystrophies. The origin of these cells had been largely unknown, but recently we identified mesenchymal progenitors positive for platelet-derived growth factor receptor alpha (PDGFRa) as the origin of adipocytes in skeletal muscle. However, the origin of muscle fibrosis remains largely unknown. In this study, clonal analyses show that PDGFRa + cells also differentiate into collagen type-I-producing cells. In fact, PDGFRa + cells accumulated in fibrotic areas of the diaphragm in the mdx mouse, a model of Duchenne muscular dystrophy. Furthermore, mRNA of fibrosis markers was expressed exclusively in the PDGFRa + cell fraction in the mdx diaphragm. Importantly, TGF-b isoforms, known as potent profibrotic cytokines, induced expression of markers of fibrosis in PDGFRa + cells but not in myogenic cells. Transplantation studies revealed that fibrogenic PDGFRa + cells mainly derived from pre-existing PDGFRa + cells and that the contribution of PDGFRa 2 cells and circulating cells was limited. These results indicate that mesenchymal progenitors are the main origin of not only fat accumulation but also fibrosis in skeletal muscle.

Duchenne muscular dystrophy (DMD) is the most common lethal genetic disorder of children. The mdx (C57BL/10 background, C57BL/10-mdx) mouse is a widely used model of DMD, but the histopathological hallmarks of DMD, such as the smaller number of myofibers, accumulation of fat and fibrosis, and insufficient regeneration of myofibers, are not observed in adult C57BL/10-mdx except for in the diaphragm. In this study, we showed that DBA/2 mice exhibited decreased muscle weight, as well as lower myofiber numbers after repeated degeneration-regeneration cycles. Furthermore, the self-renewal efficiency of satellite cells of DBA/2 is lower than that of C57BL/6. Therefore, we produced a DBA/2-mdx strain by crossing DBA/2 and C57BL/10-mdx. The hind limb muscles of DBA/2-mdx mice exhibited lower muscle weight, fewer myofibers, and increased fat and fibrosis, in comparison with C57BL/10-mdx. Moreover, remarkable muscle weakness was observed in DBA/ 2-mdx. These results indicate that the DBA/2-mdx mouse is a more suitable model for DMD studies, and the efficient satellite cell self-renewal ability of C57BL/10-mdx might explain the difference in pathologies between humans and mice. (Am J Pathol

No abstract

SUMMARYSatellite cells, which are skeletal muscle stem cells, divide to provide new myonuclei to growing muscle fibers during postnatal development, and then are maintained in an undifferentiated quiescent state in adult skeletal muscle. This state is considered to be essential for the maintenance of satellite cells, but their molecular regulation is unknown. We show that Hesr1 (Hey1) and Hesr3 (Heyl) (which are known Notch target genes) are expressed simultaneously in skeletal muscle only in satellite cells. In Hesr1 and Hesr3 single-knockout mice, no obvious abnormalities of satellite cells or muscle regenerative potentials are observed. However, the generation of undifferentiated quiescent satellite cells is impaired during postnatal development in Hesr1/3 doubleknockout mice. As a result, myogenic (MyoD and myogenin) and proliferative (Ki67) proteins are expressed in adult satellite cells. Consistent with the in vivo results, Hesr1/3-null myoblasts generate very few Pax7 + MyoD -undifferentiated cells in vitro. Furthermore, the satellite cell number gradually decreases in Hesr1/3 double-knockout mice even after it has stabilized in control mice, and an age-dependent regeneration defect is observed. In vivo results suggest that premature differentiation, but not cell death, is the reason for the reduced number of satellite cells in Hesr1/3 double-knockout mice. These results indicate that Hesr1 and Hesr3 are essential for the generation of adult satellite cells and for the maintenance of skeletal muscle homeostasis. KEY WORDS: Satellite cells, Undifferentiated quiescent state, Hesr1 (Hey1), Hesr3 (Heyl), MouseHesr1 and Hesr3 are essential to generate undifferentiated quiescent satellite cells and to maintain satellite cell numbers

Objective-Obesity is recognized increasingly as a major risk factor for kidney disease. We reported previously that plasma adiponectin levels were decreased in obesity, and that adiponectin had defensive properties against type 2 diabetes and hypertension. In this study, we investigated the role of adiponectin for kidney disease in a subtotal nephrectomized mouse model. Methods and Results-Subtotal (5/6) nephrectomy was performed in adiponectin-knockout (APN-KO) and wild-type (WT) mice. The procedure resulted in significant accumulation of adiponectin in glomeruli and interstitium in the remnant kidney. Urinary albumin excretion, glomerular hypertrophy, and tubulointerstitial fibrosis were significantly worse in APN-KO mice compared with WT mice. Intraglomerular macrophage infiltration and mRNA levels of vascular cell adhesion molecule (VCAM)-1, MCP-1, tumor necrosis factor (TNF)-␣, transforming growth factor (TGF)-␤1, collagen type I/III, and NADPH oxidase components were significantly increased in KO mice compared with WT mice. Treatment of APN-KO mice with adenovirus-mediated adiponectin resulted in amelioration of albuminuria, glomerular hypertrophy, and tubulointerstitial fibrosis and reduced the elevated levels of VCAM-1, MCP-1, TNF-␣, TGF-␤1, collagen type I/III, and NADPH oxidase components mRNAs to the same levels as those in WT mice. Conclusions-Adiponectin accumulates to the injured kidney, and prevents glomerular and tubulointerstitial injury through modulating inflammation and oxidative stress. Key Words: adiponectin Ⅲ obesity Ⅲ subtotal nephrectomy Ⅲ inflammation Ⅲ oxidative stress O besity is recognized increasingly as a major risk factor for kidney disease. It has been reported that body mass index (BMI) was associated significantly with increased risk for chronic kidney disease after adjusting for the other confounders. 1 The adipose tissue produces and secretes many bioactive substances, known as adipocytokines, which directly contribute to obesity-linked metabolic and vascular diseases. Adiponectin is an adipocyte-specific plasma protein that was identified in our laboratories in a human adipose tissue cDNA library. 2 In a series of publications, we reported that physiological concentrations of human recombinant adiponectin suppressed the expression of endothelial adhesion molecules, vascular smooth muscle cell (VSMC) proliferation, macrophage-to-foam cell transformation, and tumor necrosis factor (TNF)-␣ production by macrophages in vitro. [3][4][5] We have also shown that adiponectin selectively increased the expression of tissue inhibitor of metalloproteinases, which inhibits extracellular matrix degradation and protects the vascular wall from plaque disruption, in human monocyte-derived macrophages through interleukin (IL)-10 induction, an antiinflammatory cytokine. 6 Recently, it has been reported that adiponectin exhibited cardioprotective effects after myocardial ischemia/reperfusion through the reduction of oxidative stress. 7 In human studies, we also reported the presence of hypoadip...