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  • 1
    Online Resource
    Online Resource
    α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure
    Springer Science and Business Media LLC ; 2023
    In:  Cell Research Vol. 33, No. 9 ( 2023-07-13), p. 679-698
    Details
    In: Cell Research, Springer Science and Business Media LLC, Vol. 33, No. 9 ( 2023-07-13), p. 679-698
    Abstract: The sarcomeric interaction of α-myosin heavy chain (α-MHC) with Titin is vital for cardiac structure and contraction. However, the mechanism regulating this interaction in normal and failing hearts remains unknown. Lactate is a crucial energy substrate of the heart. Here, we identify that α-MHC undergoes lactylation on lysine 1897 to regulate the interaction of α-MHC with Titin. We observed a reduction of α-MHC K1897 lactylation in mice and patients with heart failure. Loss of K1897 lactylation in α-MHC K1897R knock-in mice reduces α-MHC–Titin interaction and leads to impaired cardiac structure and function. Furthermore, we identified that p300 and Sirtuin 1 act as the acyltransferase and delactylase of α-MHC, respectively. Decreasing lactate production by chemical or genetic manipulation reduces α-MHC lactylation, impairs α-MHC–Titin interaction and worsens heart failure. By contrast, upregulation of the lactate concentration by administering sodium lactate or inhibiting the pivotal lactate transporter in cardiomyocytes can promote α-MHC K1897 lactylation and α-MHC–Titin interaction, thereby alleviating heart failure. In conclusion, α-MHC lactylation is dynamically regulated and an important determinant of overall cardiac structure and function. Excessive lactate efflux and consumption by cardiomyocytes may decrease the intracellular lactate level, which is the main cause of reduced α-MHC K1897 lactylation during myocardial injury. Our study reveals that cardiac metabolism directly modulates the sarcomeric structure and function through lactate-dependent modification of α-MHC.
    Type of Medium: Online Resource
    ISSN: 1748-7838
    URL: Article
    DOI: 10.1038/s41422-023-00844-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2082402-6
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  • 2
    Online Resource
    Online Resource
    HuR-mediated nucleocytoplasmic translocation of HOTAIR relieves its inhibition of osteogenic differentiation and promotes bone formation
    Springer Science and Business Media LLC ; 2023
    In:  Bone Research Vol. 11, No. 1 ( 2023-10-23)
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    In: Bone Research, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2023-10-23)
    Abstract: Bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation and osteoblast function play critical roles in bone formation, which is a highly regulated process. Long noncoding RNAs (lncRNAs) perform diverse functions in a variety of biological processes, including BMSC osteogenic differentiation. Although several studies have reported that HOX transcript antisense RNA (HOTAIR) is involved in BMSC osteogenic differentiation, its effect on bone formation in vivo remains unclear. Here, by constructing transgenic mice with BMSC (Prx1-HOTAIR)- and osteoblast (Bglap-HOTAIR)-specific overexpression of HOTAIR, we found that Prx1-HOTAIR and Bglap-HOTAIR transgenic mice show different bone phenotypes in vivo. Specifically, Prx1-HOTAIR mice showed delayed bone formation, while Bglap-HOTAIR mice showed increased bone formation. HOTAIR inhibits BMSC osteogenic differentiation but promotes osteoblast function in vitro. Furthermore, we identified that HOTAIR is mainly located in the nucleus of BMSCs and in the cytoplasm of osteoblasts. HOTAIR displays a nucleocytoplasmic translocation pattern during BMSC osteogenic differentiation. We first identified that the RNA-binding protein human antigen R (HuR) is responsible for HOTAIR nucleocytoplasmic translocation. HOTAIR is essential for osteoblast function, and cytoplasmic HOTAIR binds to miR-214 and acts as a ceRNA to increase Atf4 protein levels and osteoblast function. Bglap-HOTAIR mice, but not Prx1-HOTAIR mice, showed alleviation of bone loss induced by unloading. This study reveals the importance of temporal and spatial regulation of HOTAIR in BMSC osteogenic differentiation and bone formation, which provides new insights into precise regulation as a target for bone loss.
    Type of Medium: Online Resource
    ISSN: 2095-6231
    URL: Article
    DOI: 10.1038/s41413-023-00289-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2803313-9
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  • 3
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    Online Resource
    The mechanosensitive lncRNA Neat1 promotes osteoblast function through paraspeckle-dependent Smurf1 mRNA retention
    Springer Science and Business Media LLC ; 2022
    In:  Bone Research Vol. 10, No. 1 ( 2022-02-24)
    Details
    In: Bone Research, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2022-02-24)
    Abstract: Mechanical stimulation plays an important role in bone remodeling. Exercise-induced mechanical loading enhances bone strength, whereas mechanical unloading leads to bone loss. Increasing evidence has demonstrated that long noncoding RNAs (lncRNAs) play key roles in diverse biological, physiological and pathological contexts. However, the roles of lncRNAs in mechanotransduction and their relationships with bone formation remain unknown. In this study, we screened mechanosensing lncRNAs in osteoblasts and identified Neat1 , the most clearly decreased lncRNA under simulated microgravity. Of note, not only Neat1 expression but also the specific paraspeckle structure formed by Neat1 was sensitive to different mechanical stimulations, which were closely associated with osteoblast function. Paraspeckles exhibited small punctate aggregates under simulated microgravity and elongated prolate or larger irregular structures under mechanical loading. Neat1 knockout mice displayed disrupted bone formation, impaired bone structure and strength, and reduced bone mass. Neat1 deficiency in osteoblasts reduced the response of osteoblasts to mechanical stimulation. In vivo, Neat1 knockout in mice weakened the bone phenotypes in response to mechanical loading and hindlimb unloading stimulation. Mechanistically, paraspeckles promoted nuclear retention of E3 ubiquitin ligase Smurf1 mRNA and downregulation of their translation, thus inhibiting ubiquitination-mediated degradation of the osteoblast master transcription factor Runx2, a Smurf1 target. Our study revealed that Neat1 plays an essential role in osteoblast function under mechanical stimulation, which provides a paradigm for the function of the lncRNA-assembled structure in response to mechanical stimulation and offers a therapeutic strategy for long-term spaceflight- or bedrest-induced bone loss and age-related osteoporosis.
    Type of Medium: Online Resource
    ISSN: 2095-6231
    URL: Article
    DOI: 10.1038/s41413-022-00191-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2803313-9
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