Age-associated muscle atrophy is a debilitating condition associated with loss of muscle mass and function with age that contributes to limitation of mobility and locomotion. However, the underlying ...mechanisms of how intrinsic muscle changes with age are largely unknown. Here we report that, with age, Mind bomb-1 (Mib1) plays important role in skeletal muscle maintenance via proteasomal degradation-dependent regulation of α-actinin 3 (Actn3). The disruption of Mib1 in myofibers (Mib1
) results in alteration of type 2 glycolytic myofibers, muscle atrophy, impaired muscle function, and Actn3 accumulation. After chronic exercise, Mib1
mice show muscle atrophy even at young age. However, when Actn3 level is downregulated, chronic exercise-induced muscle atrophy is ameliorated. Importantly, the Mib1 and Actn3 levels show clinical relevance in human skeletal muscles accompanied by decrease in skeletal muscle function with age. Together, these findings reveal the significance of the Mib1-Actn3 axis in skeletal muscle maintenance with age and suggest the therapeutic potential for the treatment or amelioration of age-related muscle atrophy.
Mammary glands develop through primary ductal elongation and side branching to maximize the spatial area. Although primary ducts are generated by bifurcation of terminal end buds, the mechanism ...through which side branching occurs is still largely unclear. Here, we show that inhibitor of DNA-binding 2 (ID2) drives side branch formation through the differentiation of K6
bipotent progenitor cells (BPs) into CD61
luminal progenitor cells (LPs).
-null mice had side-branching defects, along with developmental blockage of the differentiation of K6
BPs into CD61
LPs. Notably, CD61
LPs were found in budding and side branches, but not in terminal end buds. Hormone reconstitution studies using ovariectomized MMTV-hemagglutinin-nuclear localized sequence-tagged
transgenic mice revealed that ID2 is a key mediator of progesterone, which drives luminal lineage differentiation and side branching. Our results suggest that CD61 is a marker of side branches and that ID2 regulates side branch formation by inducing luminal lineage commitment from K6
BPs to CD61
LPs.
The survival of motor neuron (SMN) protein is a major component of the pre-mRNA splicing machinery and is required for RNA metabolism. Although SMN has been considered a fundamental gene for the ...central nervous system, due to its relationship with neuromuscular diseases, such as spinal muscular atrophy, recent studies have also revealed the requirement of SMN in non-neuronal cells in the peripheral regions. Here, we report that the fibro-adipogenic progenitor subpopulation expressing Dpp4 (Dpp4+ FAPs) is required for the neuromuscular system. Furthermore, we also reveal that BRCA1-associated protein-1 (Bap1) is crucial for the stabilization of SMN in FAPs by preventing its ubiquitination-dependent degradation. Inactivation of Bap1 in FAPs decreased SMN levels and accompanied degeneration of the neuromuscular junction, leading to loss of motor neurons and muscle atrophy. Overexpression of the ubiquitination-resistant SMN variant, SMNK186R, in Bap1-null FAPs completely prevented neuromuscular degeneration. In addition, transplantation of Dpp4+ FAPs, but not Dpp4- FAPs, completely rescued neuromuscular defects. Our data reveal the crucial role of Bap1-mediated SMN stabilization in Dpp4+ FAPs for the neuromuscular system and provide the possibility of cell-based therapeutics to treat neuromuscular diseases.
Background
With organismal aging, the hypothalamic–pituitary–gonadal (HPG) activity gradually decreases, resulting in the systemic functional declines of the target tissues including skeletal ...muscles. Although the HPG axis plays an important role in health span, how the HPG axis systemically prevents functional aging is largely unknown.
Methods
We generated muscle stem cell (MuSC)‐specific androgen receptor (Ar) and oestrogen receptor 2 (Esr2) double knockout (dKO) mice and pharmacologically inhibited (Antide) the HPG axis to mimic decreased serum levels of sex steroid hormones in aged mice. After short‐term and long‐term sex hormone signalling ablation, the MuSCs were functionally analysed, and their aging phenotypes were compared with those of geriatric mice (30‐month‐old). To investigate pathways associated with sex hormone signalling disruption, RNA sequencing and bioinformatic analyses were performed.
Results
Disrupting the HPG axis results in impaired muscle regeneration wild‐type (WT) vs. dKO, P < 0.0001; Veh vs. Antide, P = 0.004. The expression of DNA damage marker (in WT = 7.0 ± 1.6%, dKO = 32.5 ± 2.6%, P < 0.01; in Veh = 13.4 ± 4.5%, Antide = 29.7 ± 5.5%, P = 0.028) and senescence‐associated β‐galactosidase activity (in WT = 3.8 ± 1.2%, dKO = 10.3 ± 1.6%, P < 0.01; in Veh = 2.1 ± 0.4%, Antide = 9.6 ± 0.8%, P = 0.005), as well as the expression levels of senescence‐associated genes, p16Ink4a and p21Cip1, was significantly increased in the MuSCs, indicating that genetic and pharmacological inhibition of the HPG axis recapitulates the progressive aging process of MuSCs. Mechanistically, the ablation of sex hormone signalling reduced the expression of transcription factor EB (Tfeb) and Tfeb target gene in MuSCs, suggesting that sex hormones directly induce the expression of Tfeb, a master regulator of the autophagy–lysosome pathway, and consequently autophagosome clearance. Transduction of the Tfeb in naturally aged MuSCs increased muscle mass control geriatric MuSC transplanted tibialis anterior (TA) muscle = 34.3 ± 2.9 mg, Tfeb‐transducing geriatric MuSC transplanted TA muscle = 44.7 ± 6.7 mg, P = 0.015 and regenerating myofibre size eMyHC+tdTomato+ myofibre cross‐section area (CSA) in control vs. Tfeb, P = 0.002 after muscle injury.
Conclusions
Our data show that the HPG axis systemically controls autophagosome clearance in MuSCs through Tfeb and prevents MuSCs from senescence, suggesting that sustained HPG activity throughout life regulates autophagosome clearance to maintain the quiescence of MuSCs by preventing senescence until advanced age.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Myogenic progenitors (MPs) generate myocytes that fuse to form myofibers during skeletal muscle development while maintaining the progenitor pool, which is crucial for generating sufficient muscle. ...Notch signaling has been known to reserve a population of embryonic MPs during primary myogenesis by promoting cell cycle exit and suppressing premature differentiation. However, the roles of individual Notch receptors (Notch1-4) during embryonic/fetal myogenesis are still elusive. In this study, we found that Notch1 and Notch2, which exhibit the highest structural similarity among Notch receptors, maintain the MP population by distinct mechanisms: Notch1 induces cell cycle exit and Notch2 suppresses premature differentiation. Moreover, genetic and cell culture studies showed that Notch1 and Notch2 signaling in MPs are distinctively activated by interacting with Notch ligand-expressing myofibers and MP-lineage cells, respectively. These results suggest that through different activation modes, Notch1 and Notch2 distinctively and cooperatively maintain MP population during fetal myogenesis for proper muscle development.
Quiescent satellite cells, known as adult muscle stem cells, possess a remarkable ability to regenerate skeletal muscle following injury throughout life. Although they mainly originate from ...multipotent stem/progenitor cells of the somite, the mechanism underlying the establishment of quiescent satellite cell populations is unknown. Here, we show that sex hormones induce Mind bomb 1 (Mib1) expression in myofibres at puberty, which activates Notch signalling in cycling juvenile satellite cells and causes them to be converted into adult quiescent satellite cells. Myofibres lacking Mib1 fail to send Notch signals to juvenile satellite cells, leading to impaired cell cycle exit and depletion. Our findings reveal that the hypothalamic-pituitary-gonadal axis drives Mib1 expression in the myofibre niche. Moreover, the same axis regulates the re-establishment of quiescent satellite cell populations following injury. Our data show that sex hormones establish adult quiescent satellite cell populations by regulating the myofibre niche at puberty and re-establish them during regeneration.
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IJS, NUK, SBMB, UL, UM, UPUK
During exercise, skeletal muscle is exposed to a low oxygen condition, hypoxia. Under hypoxia, the transcription factor hypoxia-inducible factor-1α (HIF-1α) is stabilized and induces expressions of ...its target genes regulating glycolytic metabolism. Here, using a skeletal muscle-specific gene ablation mouse model, we show that Brg1/Brm-associated factor 155 (Baf155), a core subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, is essential for HIF-1α signaling in skeletal muscle. Muscle-specific ablation of Baf155 increases oxidative metabolism by reducing HIF-1α function, which accompanies the decreased lactate production during exercise. Furthermore, the augmented oxidation leads to high intramuscular adenosine triphosphate (ATP) level and results in the enhancement of endurance exercise capacity. Mechanistically, our chromatin immunoprecipitation (ChIP) analysis reveals that Baf155 modulates DNA-binding activity of HIF-1α to the promoters of its target genes. In addition, for this regulatory function, Baf155 requires a phospho-signal transducer and activator of transcription 3 (pSTAT3), which forms a coactivator complex with HIF-1α, to activate HIF-1α signaling. Our findings reveal the crucial role of Baf155 in energy metabolism of skeletal muscle and the interaction between Baf155 and hypoxia signaling.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives: In this study we examine the relationship between contextual factors, that is, perceived multicultural norms, and immigrant well-being. Specifically, we test a model whereby each of the ...three dimensions of normative multiculturalism, perceived Multicultural Ideology, Multicultural Policies and Practices, and Multicultural Contact, positively predicts immigrant well-being both directly and indirectly via belongingness. Method: Korean immigrants in New Zealand (N = 306, 56% female) participated in the research. Their average age was 31.17 (SD = 10.46), and the average length of residence was 10.04 years (SD = 7.21). Participants completed a survey that included the Normative Multiculturalism Scale along with measures of belonging and well-being (flourishing, life satisfaction, and positive affect). Results: Structural equation modeling showed that perceived normative Multicultural Policies and Practices exerted a direct positive effect on well-being and an indirect positive effect via belongingness; Multicultural Ideology exerted only an indirect effect; and Multicultural Contact did not significantly relate to belongingness or subjective well-being. Implications: The results are discussed in terms of everyday experiences of intercultural encounters, social norms and the contextual influences of diversity climates, as well as the importance of distinguishing the defining features of multiculturalism in diversity science research. We also propose that multicultural norm setting and norms marketing may lead to positive social and psychological outcomes for immigrants.
Public Significance Statement
Findings indicate that the extent to which immigrants perceive widespread appreciation of cultural diversity and policies and practices to ensure cultural maintenance and equitable participation, is conducive to immigrants' sense of belongingness and psychological well-being.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK
Unlike other G protein-coupled receptor (GPR)119 agonists, DA-1241 has shown long-term beneficial effects on glucose and lipid metabolism in previous studies. In this study, we investigated the ...antidiabetic effects of DA-1241 in vitro and in vivo. The efficacy of DA-1241 was evaluated by assessing the changes in glucagon-like peptide-1 (GLP-1) levels, gluconeogenesis, and hepatic autophagy. DA-1241 was administrated to high-fat diet (HFD)-fed C57BL/6J mice for 12 weeks (n=34), and serum insulin and GLP-1 levels were measured by oral glucose tolerance tests at week 8. The effects of DA-1241 on gluconeogenic enzyme expression and autophagic flow were evaluated in HepG2 cells and livers isolated from LC3-GFP-transgenic mice. DA-1241 improved oral glucose tolerance (no significant effect on intraperitoneal glucose tolerance test) with an increase in serum GLP-1 and insulin levels. Fasting blood glucose level decreased, and the insulinogenic index was improved after DA-1241 treatment in HFD-fed mice. However, no significant increase in insulin secretion in INS1E cells and isolated mouse islet with DA1241 treatment. DA-1241 reduced gluconeogenic enzyme expression and blocked autophagic flow in HepG2 cells. Additionally, DA1241 induced GFP fragmentation in liver from LC3-GFP-transgenic mice. These findings suggested that DA-1241 augmented glucose-dependent insulin release via improvement in GLP-1 secretion, and reduced hepatic gluconeogenesis, which might be associated with autophagic blockage, leading to improved glycaemic control.
Disclosure
J. Kim: None. Y. Kim: None. R. Kim: None. M. Kim: None. H. Park: None. M. Lee: None. Y. Cho: None. J. Bae: None. S. Lee: None. I. Lee: None. H. Lee: None. C. Kim: None. E. Kang: None.
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