Sestrin prevents skeletal muscle atrophy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA563889 | ENA |
REPOSITORIES: ENA
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Project description:Skeletal muscle atrophy is a serious and highly prevalent condition that remains poorly understood at the molecular level. Previous work found that skeletal muscle atrophy involves an increase in skeletal muscle Gadd45a expression, which is necessary and sufficient for skeletal muscle fiber atrophy. However, the direct mechanism by which Gadd45a promotes skeletal muscle atrophy was unknown. To address this question, we biochemically isolated skeletal muscle fiber proteins that associate with Gadd45a as it induces skeletal muscle atrophy in living mice. We found that Gadd45a interacts with multiple proteins in skeletal muscle fibers, including, most prominently, the MAP kinase kinase kinase MEKK4. Furthermore, by forming a complex with MEKK4 in skeletal muscle fibers, Gadd45a increases MEKK4 protein kinase activity, which is sufficient to induce skeletal muscle fiber atrophy and required for Gadd45a-mediated skeletal muscle fiber atrophy. Together, these results identify a direct biochemical mechanism by which Gadd45a induces skeletal muscle atrophy and provide new insight into way that skeletal muscle atrophy occurs at the molecular level.
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Project description:Current atlas of regulatory sequences controlling skeletal muscle atrophy are still incomplete and lack cell type resolution. We applied single-cell chromatin accessibility assays (snATAC) to normal and denervated skeletal muscle from mice. We integrated these snATAC datasets with our single-nucleus RNA-sequence dataset to reveal the status of open chromatin. Using these datasets, we delineated chromatin accessibility maps in both normal and atrophic muscles and identified cis-regulatory elements (CREs) in all type of cell in skeletal muscle that may regulating muscle protein metabolism, energy metabolism and transcription activities, thus, provided a rich resource for understanding gene regulatory programs in skeletal muscle and related disorders.
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Project description:p53 regulates a distinct subset of skeletal muscle mRNAs during immobilization-induced skeletal muscle atrophy For additional details see Fox et al, p53 and ATF4 mediate distinct and additive pathways to skeletal muscle atrophy during limb immobilization. Am J Physiol Endocrinol Metab. 2014 Aug 1;307(3):E245-61. Bilateral tibialis anterior muscles were harvested at three days for the following conditions: 1) hindlimb immobilization of C57BL/6 mice; 2) hindlimb immobilization of p53 mKO and littermate control mice; 3) transfection of wild type mice with p53 plasmid or control plasmid
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