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Reprogramming of cis-regulatory networks during skeletal muscle atrophy in male mice.

ABSTRACT: A comprehensive atlas of cis-regulatory elements and their dynamic activity is necessary to understand the transcriptional basis of cellular structure maintenance, metabolism, and responses to the environment. Here we show, using matched single-nucleus chromatin accessibility and RNA-sequencing from juvenile male C57BL6 mice, an atlas of accessible chromatin regions in both normal and denervated skeletal muscles. We identified cell-type-specific cis-regulatory networks, highlighting the dynamic regulatory circuits mediating transitions between myonuclear types. Through comparison of normal and perturbed muscle, we delineated the reprogramming of cis-regulatory networks in response to denervation, described the interplay of promoters/enhancers and target genes. We further unveil a hierarchical structure of transcription factors that delineate a regulatory network in atrophic muscle, identifying ELK4 as a key atrophy-related transcription factor that instigates muscle atrophy through TGF-β1 regulation. This study furnishes a rich genomic resource, essential for decoding the regulatory dynamics of skeletal muscle in both physiological and pathological states.

SUBMITTER: Lin H

PROVIDER: S-EPMC10584982 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Reprogramming of cis-regulatory networks during skeletal muscle atrophy in male mice.

Lin Hongchun H Peng Hui H Sun Yuxiang Y Si Meijun M Wu Jiao J Wang Yanlin Y Thomas Sandhya S SS Sun Zheng Z Hu Zhaoyong Z

Nature communications 20231018 1

A comprehensive atlas of cis-regulatory elements and their dynamic activity is necessary to understand the transcriptional basis of cellular structure maintenance, metabolism, and responses to the environment. Here we show, using matched single-nucleus chromatin accessibility and RNA-sequencing from juvenile male C57BL6 mice, an atlas of accessible chromatin regions in both normal and denervated skeletal muscles. We identified cell-type-specific cis-regulatory networks, highlighting the dynamic ...[more]

PMID: 37853001

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Project description:During aging, muscle mass decreases, leading to sarcopenia, associated with low-level chronic inflammation (inflammaging), which induces sarcopenia by promoting proteolysis of muscle fibers and inhibiting their regeneration. Patients with a variety of pathologic conditions associated with sarcopenia, including rheumatoid arthritis (RA), have systemically elevated TNFα serum levels, and transgenic mice with TNFα overexpression (TNF-Tg mice, a model of RA) develop sarcopenia between adolescence and adulthood before they age. However, if and how TNFα contributes to the pathogenesis of sarcopenia during the normal aging process and in RA remains largely unknown. We report that TNFα levels are increased in skeletal muscles of aged WT mice, associated with muscle atrophy and decreased numbers of satellite cells and Type IIA myofibers, a phenotype that we also observed in adult TNF-Tg mice. Aged WT mice also have increased numbers of myeloid lineage cells in their skeletal muscles, including macrophages and granulocytes. These cells have increased TNFα expression, which impairs myogenic cell differentiation. Expression levels of TNF receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase, which mediates signaling by some TNF receptor (TNFR) family members, are elevated in skeletal muscles of both aged WT mice and adult TNF-Tg mice. TRAF6 binds to TNFR2 in C2C12 myoblasts and mediates TNFα-induced muscle atrophy through NF-κB-induced transcription of the muscle-specific E3 ligases, Atrogen1 and Murf1, which promote myosin heavy-chain degradation. Haplo-deficiency of TRAF6 prevents muscle atrophy and the decrease in numbers of satellite cells, Type IIA myofibers, and myogenic regeneration in TRAF6+/- ;TNF-Tg mice. Our findings suggest that pharmacologic inhibition of TRAF6 signaling in skeletal muscles during aging could treat/prevent age- and RA-related sarcopenia by preventing TNFα-induced proteolysis and inhibition of muscle fiber regeneration. © 2020 American Society for Bone and Mineral Research.

Dataset Information

Reprogramming of cis-regulatory networks during skeletal muscle atrophy in male mice.

Publications

Reprogramming of cis-regulatory networks during skeletal muscle atrophy in male mice.

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