Skeletal muscle has remarkable regeneration capabilities, mainly due to its resident muscle stem cells (MuSCs). In this review, we introduce recently developed technologies and the mechanistic insights they provide to the understanding of MuSC biology, including the re-definition of quiescence and Galert states. Additionally, we present recent studies that link MuSC function with cellular heterogeneity, highlighting the complex regulation of self-renewal in regeneration, muscle disorders and aging. Finally, we discuss MuSC metabolism and its role, as well as the multifaceted regulation of MuSCs by their niche. The presented conceptual advances in the MuSC field impact on our general understanding of stem cells and their therapeutic use in regenerative medicine.
Impaired adipogenesis renders an adipose tissue unable to expand, leading to lipotoxicity and conditions such as diabetes and cardiovascular disease. While factors important for adipogenesis have been studied extensively, those that set the limits of adipose tissue expansion remain undetermined. Feeding a Western-type diet to apolipoprotein E2 knock-in mice, a model of metabolic syndrome, produced 3 groups of equally obese mice: mice with normal glucose tolerance, hyperinsulinemic yet glucose-tolerant mice, and prediabetic mice with impaired glucose tolerance and reduced circulating insulin. Using proteomics, we compared subcutaneous adipose tissues from mice in these groups and found that the expression of PTRF (polymerase I and transcript release factor) associated selectively with their glucose tolerance status. Lentiviral and pharmacologically overexpressed PTRF, whose function is critical for caveola formation, compromised adipocyte differentiation of cultured 3T3-L1cells. In human adipose tissue, PTRF mRNA levels positively correlated with markers of lipolysis and cellular senescence. Furthermore, a negative relationship between telomere length and PTRF mRNA levels was observed in human subcutaneous fat. PTRF is associated with limited adipose tissue expansion underpinning the key role of caveolae in adipocyte regulation. Furthermore, PTRF may be a suitable adipocyte marker for predicting pathological obesity and inform clinical management.
Background The Apolipoprotein E (APOE) gene encodes for three isoforms in the human population (APOE2, APOE3, and APOE4). While the role of APOE in lipid metabolism is well characterized, the specific metabolic signatures of the APOE isoforms, during metabolic disorders, remain unclear. Objective To elucidate the molecular underpinnings of APOE-directed metabolic alterations, we tested the hypothesis that APOE4 drives a whole-body metabolic shift toward increased lipid oxidation. Methods We employed humanized mice in which Apoe gene has been replaced by the human APOE*3 or APOE*4 allele to produce human APOE3 or APOE4 proteins and characterized several mechanisms of fatty acid oxidation, lipid storage, substrate utilization and thermogenesis in those mice. Results We show that while APOE4 mice gained less body weight and mass than their APOE3 counterparts on a Western-type diet (p<0.001), they displayed elevated insulin and HOMA, markers of insulin resistance (p=0.004 and p=0.025, respectively). APOE4 mice also demonstrated a reduced respiratory quotient during the postprandial period (0.95±0.03 vs. 1.06±0.03, p<0.001), indicating increased usage of lipids as opposed to carbohydrates as a fuel source. Finally, APOE4 mice showed increased body temperature (37.30 ± 0.68 vs 36.9 ± 0.58 °C, p=0.039), augmented cold tolerance, and more metabolically active brown adipose tissue compared to APOE3 mice. Conclusion These data suggest that APOE4 mice may resist weight gain via an APOE4-directed global metabolic shift toward lipid oxidation and enhanced thermogenesis, and may represent a critical first step in the development of APOE-directed therapies for a large percentage of the population affected by disorders with established links to APOE and metabolism.
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