AMP-activated Protein Kinase Regulates β-Catenin Transcription via Histone Deacetylase 5

Zhao, Junxing; Yue, Wan‐Fu; Zhu, Mei‐Jun; Du, Min

doi:10.1074/jbc.m110.199372

Cited by 51 publications

(61 citation statements)

References 65 publications

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“…AMPK has also been shown to modulate the Wingless Int-1 (Wnt) signaling pathway (23)(24)(25), which is implicated in the pathogenesis of OA (26). Wnt stimulation in cartilage promotes the accumulation and nuclear translocation of β-catenin, an effector of Wnt signaling, where it activates the expression of catabolic target genes such as metalloproteinases (26).…”

Section: Resultsmentioning

confidence: 99%

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury

Yan

Duan

Pan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

113

121

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Osteoarthritis (OA) is a major cause of disability and morbidity in the aging population. Joint injury leads to cartilage damage, a known determinant for subsequent development of posttraumatic OA, which accounts for 12% of all OA. Understanding the early molecular and cellular responses postinjury may provide targets for therapeutic interventions that limit articular degeneration. Using a murine model of controlled knee joint impact injury that allows the examination of cartilage responses to injury at specific time points, we show that intraarticular delivery of a peptidic nanoparticle complexed to NF-κB siRNA significantly reduces early chondrocyte apoptosis and reactive synovitis. Our data suggest that NF-κB siRNA nanotherapy maintains cartilage homeostasis by enhancing AMPK signaling while suppressing mTORC1 and Wnt/β-catenin activity. These findings delineate an extensive crosstalk between NF-κB and signaling pathways that govern cartilage responses postinjury and suggest that delivery of NF-κB siRNA nanotherapy to attenuate early inflammation may limit the chronic consequences of joint injury. Therapeutic benefits of siRNA nanotherapy may also apply to primary OA in which NF-κB activation mediates chondrocyte catabolic responses. Additionally, a critical barrier to the successful development of OA treatment includes ineffective delivery of therapeutic agents to the resident chondrocytes in the avascular cartilage. Here, we show that the peptide–siRNA nanocomplexes are nonimmunogenic, are freely and deeply penetrant to human OA cartilage, and persist in chondrocyte lacunae for at least 2 wk. The peptide–siRNA platform thus provides a clinically relevant and promising approach to overcoming the obstacles of drug delivery to the highly inaccessible chondrocytes.

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Section: Resultsmentioning

confidence: 99%

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury

Yan

Duan

Pan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

113

121

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“…Immunoblotting Analyses-Immunoblotting analysis was performed as previously described using an Odyssey Infrared Imaging System (LI-COR Biosciences) (27). Band density was normalized to ␤-tubulin content.…”

Section: Methodsmentioning

confidence: 99%

AMP-activated Protein Kinase Stimulates Warburg-like Glycolysis and Activation of Satellite Cells during Muscle Regeneration

Zhu

Dodson

et al. 2015

Journal of Biological Chemistry

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Background:The mechanisms eliciting metabolic activation in satellite cells are unclear. Results: Noncanonical Sonic Hedgehog is activated following muscle injury, which activates AMPK␣1 to induce Warburg-like glycolysis and promote satellite cell activation and proliferation. Conclusion: AMPK␣1 is required for Warburg-like glycolysis in satellite cells, which promotes satellite cell activation and muscle regeneration. Significance: AMPK promotes satellite cell activation during muscle regeneration.

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“…Cells grown on coverslips or multiple-well plates were fixed in 4% paraformaldehyde for 10 min, permeabilized with cold methanol for 5 min, quenched with 0.1% sodium borohydride for 5 min, and incubated with anti-MHC or mouse IgG (1:100) at 4°C overnight. Fluorescent secondary antibody (1:1,000) was then added, and stained cells were incubated at room temperature for 1 h. Fluorescence was examined by using a Leica inverted microscope (28). Fusion indexes of differentiating myoblasts were calculated by dividing the number of nuclei in MHC-positive myotubes by the total number of nuclei.…”

Section: Methodsmentioning

confidence: 99%

“…Immunoblotting analysis was performed as previously described, using an Odyssey infrared imaging system (LiCor Biosciences, Lincoln, NE) (28). Band density was normalized to ␤-tubulin content.…”

Section: Methodsmentioning

confidence: 99%

AMP-Activated Protein Kinase α1 but Not α2 Catalytic Subunit Potentiates Myogenin Expression and Myogenesis

Zhao

Zhu

et al. 2013

Molecular and Cellular Biology

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fThe link between AMP-activated protein kinase (AMPK) and myogenesis remains poorly defined. AMPK has two catalytic ␣ subunits, ␣1 and ␣2. We postulated that AMPK promotes myogenesis in an isoform-specific manner. Primary myoblasts were prepared from AMPK knockout (KO) mice and AMPK conditional KO mice, and knockout of the ␣1 but not the ␣2 subunit resulted in downregulation of myogenin and reduced myogenesis. Myogenin expression and myogenesis were nearly abolished in the absence of both AMPK␣1 and AMPK␣2, while enhanced AMPK activity promoted myogenesis and myotube formation. The AMPK␣1-specific effect on myogenesis was likely due to the dominant expression of ␣1 in myoblasts. These results were confirmed in C2C12 cells. To further evaluate the necessity of the AMPK␣1 subunit for myogenesis in vivo, we prepared both DsRed AMPK␣1 knockout myoblasts and enhanced green fluorescent protein (EGFP) wild-type myoblasts, which were cotransplanted into tibialis anterior muscle. A number of green fluorescent muscle fibers were observed, showing the fusion of engrafted wildtype myoblasts with muscle fibers; on the other hand, very few or no red muscle fibers were observed, indicating the absence of myogenic capacity of AMPK␣1 knockout myoblasts. In summary, these results indicate that AMPK activity promotes myogenesis through a mechanism mediated by AMPK␣1. Skeletal muscle, which comprises about 40% of the body mass of adults, is the main peripheral tissue responsive to insulinstimulated uptake of glucose (1) and is critical in the development of type 2 diabetes (2). Proper myogenesis is critical for fetal muscle development (3-5) and postnatal muscle growth and regeneration, which relies heavily on the myogenic differentiation of satellite cells (6-8). In improper myogenesis and muscle regeneration, damaged muscle fibers are replaced with fibric tissue, leading to muscle atrophy and aging (9-11).AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme, composed of ␣, ␤, and ␥ subunits, which plays an important role in energy metabolism (12)(13)(14). In addition to its capacity to acutely regulate the activity of metabolic enzymes through phosphorylation, AMPK is increasingly recognized for its regulatory role in gene expression, cell differentiation, and tissue development (15, 16). The role of AMPK in muscle fiber atrophy has been well defined; a number of studies demonstrated that AMPK promotes muscle protein degradation and autophagy (17) and inhibits protein synthesis (18). To date, however, the role of AMPK in myogenesis (formation of muscle fibers) has been sparsely studied. Our previous studies showed that low AMPK activity due to obesity is correlated with attenuated myogenic differentiation during fetal muscle development (19-21). We further observed that AMPK promotes myogenin expression and myogenesis through phosphorylation of histone deacetylase 5 (HDAC5) (22), suggesting that AMPK has a critical role in myogenesis.The catalytic ␣ subunit of AMPK has two isoforms, ␣1 and ␣2, which display differential...

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AMP-activated Protein Kinase Regulates β-Catenin Transcription via Histone Deacetylase 5

Cited by 51 publications

References 65 publications

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury

AMP-activated Protein Kinase Stimulates Warburg-like Glycolysis and Activation of Satellite Cells during Muscle Regeneration

AMP-Activated Protein Kinase α1 but Not α2 Catalytic Subunit Potentiates Myogenin Expression and Myogenesis

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