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.

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 -Because skeletal muscle is one of the target tissues for insulin, skeletal muscle mass might be associated with type 2 diabetes. Serum creatinine is a possible surrogate marker of skeletal muscle mass. The purpose of this study was to determine whether serum creatinine level is associated with type 2 diabetes. RESEARCH DESIGN AND METHODS -The study participants were nondiabetic Japanese men (n ϭ 8,570) aged 40 -55 years at entry. Type 2 diabetes was diagnosed if fasting plasma glucose was Ն126 mg/dl or if participants were taking oral hypoglycemic medication or insulin.RESULTS -During the 4-year follow-up period, 877 men developed type 2 diabetes. Lower serum creatinine was associated with an increased risk of type 2 diabetes. The multiple-adjusted odds ratio for those who had serum creatinine levels between 0.40 and 0.60 mg/dl was 1.91 (95% CI 1.44 -2.54) compared with those who had levels between 0.71 and 0.80 mg/dl. CONCLUSIONS -Lower serum creatinine increased the risk of type 2 diabetes. Diabetes Care 32:424-426, 2009A lthough skeletal muscle is one of the major target organs of insulin (1-3), to our knowledge, no prospective study has investigated the association between total skeletal muscle mass and type 2 diabetes. Serum creatinine is primarily a metabolite of creatine, almost all of which is located in skeletal muscle. Because the amount of creatine per unit of skeletal muscle mass is consistent and the breakdown rate of creatine is also consistent, plasma creatinine concentration is very stable and a direct reflection of skeletal muscle mass (4). If skeletal muscle mass is associated with type 2 diabetes, consequently, serum creatinine might also be associated with type 2 diabetes. Considering this hypothesis, we examined the prospective relationship between serum creatinine and type 2 diabetes in Japanese men. RESEARCH DESIGN AND METHODS -The Kansai HealthcareStudy is an ongoing cohort investigation designed to examine the risk factors for cardiometabolic diseases. The details of this study have been described previously (5). The protocol for this research was reviewed by the human subjects review committee at Osaka City University.For the current analysis, study participants consisted of 11,063 Japanese men aged 40 -55 years at entry who had fasting plasma glucose levels Ͻ126 mg/dl and serum creatinine levels Ͻ2.0 mg/dl and were not taking oral hypoglycemic medication or insulin. Follow-up examinations were conducted annually, and the follow-up period was 4 years. A total of 2,493 men were excluded because of loss to follow-up. The analytic cohort consisted of 8,570 men.Blood samples were drawn after an overnight 12-h fast. Serum creatinine was mainly measured by an enzymatic method using a Hitachi 7350 automatic chemistry analyzer (Hitachi, Tokyo, Japan). Serum creatinine was also measured by the Jaffe method in 1,770 participants. We recalibrated the Jaffe method to the enzymatic method using the following formula: serum creatinine (mg/dl, enzymatic method) ϭ 1.02 ϫ serum creatinine (mg...

We investigated the expression of G protein-coupled receptor GPR40 and GPR120 in the rat tongue. Using reverse transcription polymerase chain reaction, we detected a significant expression of GPR120 mRNA in the epithelium of the circumvallate papillae but not in the nonsensory epithelium, while the expression of GPR40 mRNA was undetectable in the sensory papillae. Western blotting analysis of colon and circumvallate papillae for GPR120 showed a protein band with a molecular weight that corresponds to that of GPR120, indicating that this antibody could recognize a native form of GPR120. Immunohistochemistry using anti-GPR120 antibody revealed GPR120 immunoreactivity in the enteroendocrine cells of the colon. Furthermore, some cells in each taste bud were stained positively with more intense labeling in the apical part of the cells. These results suggested that GPR120 is expressed in the taste cells of the circumvallate papillae to sense dietary fat, like the receptor expressed in the enteroendocrine cells.

OBJECTIVE -We prospectively assessed whether the combined measurements of fasting plasma glucose (FPG) and A1C were effective for predicting type 2 diabetes.RESEARCH DESIGN AND METHODS -Study participants included 6,736 nondiabetic Japanese men aged 40 -55 years. Type 2 diabetes was diagnosed in those who had an FPG Ն126 mg/dl or who were being treated with an oral antidiabetic agent or insulin. The models including FPG, A1C, and both were compared using the area under the receiver operating characteristic (AUROC) curves.RESULTS -During the 4-year follow-up period, we confirmed 659 diabetes cases. In multivariate analysis, both FPG and A1C were independently associated with the risk of type 2 diabetes. The model including both FPG and A1C had a greater AUROC curve than that including FPG alone (0.853 vs. 0.818; P Ͻ 0.001) or A1C alone (0.853 vs. 0.771; P Ͻ 0.001).CONCLUSIONS -The combined measurement of FPG and A1C was effective for predicting type 2 diabetes. Diabetes Care 32:644-646, 2009