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Cited by 17Muscle Physiology and DisordersMitochondrial Function and PathologyMetabolism and Genetic Disorders

Integrated Multiomics Analysis Identifies Molecular Landscape Perturbations during Hyperammonemia in Skeletal Muscle and Myotubes

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Welch, Nicole, Singh, Shashi Shekhar, Kumar, Avinash, Dhruba, Saugato Rahman, Mishra, Saurabh, Sekar, Jinendiran, Bellar, Annette, Attaway, Amy H. +11 more·2021·Journal of Biological Chemistry
DOI 10.1016/j.jbc.2021.101023PMC PMC8424232
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Abstract

Ammonia is a cytotoxic molecule generated during normal cellular functions. Dysregulated ammonia metabolism, which is evident in many chronic diseases such as liver cirrhosis, heart failure, and chronic obstructive pulmonary disease, initiates a hyperammonemic stress response in tissues including skeletal muscle and in myotubes. Perturbations in levels of specific regulatory molecules have been reported, but the global responses to hyperammonemia are unclear. In this study, we used a multiomics approach to vertically integrate unbiased data generated using an assay for transposase-accessible chromatin with high-throughput sequencing, RNA-Seq, and proteomics. We then horizontally integrated these data across different models of hyperammonemia, including myotubes and mouse and human muscle tissues. Changes in chromatin accessibility and/or expression of genes resulted in distinct clusters of temporal molecular changes including transient, persistent, and delayed responses during hyperammonemia in myotubes. Known responses to hyperammonemia, including mitochondrial and oxidative dysfunction, protein homeostasis disruption, and oxidative stress pathway activation, were enriched in our datasets. During hyperammonemia, pathways that impact skeletal muscle structure and function that were consistently enriched were those that contribute to mitochondrial dysfunction, oxidative stress, and senescence. We made several novel observations, including an enrichment in antiapoptotic B-cell leukemia/lymphoma 2 family protein expression, increased calcium flux, and increased protein glycosylation in myotubes and muscle tissue upon hyperammonemia. Critical molecules in these pathways were validated experimentally. Human skeletal muscle from patients with cirrhosis displayed similar responses, establishing translational relevance. These data demonstrate complex molecular interactions during adaptive and maladaptive responses during the cellular stress response to hyperammonemia.

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  • Hyperammonemic stress is associated with COPD, and a recent study evidenced new pathways associated with hyperammonemia in skeletal muscle, such as antiapoptotic B-cell leukemia/lymphoma 2 family protein expression, increased calcium flux, and increased protein glycosylation.

    “Hyperammonemic stress is also known to be associated with COPD, and a recent study evidenced new pathways associated with hyperammonemia in skeletal muscle (in addition to the already-known mitochondrial dysfunction, oxidative stress, and senescence), such as antiapoptotic B-cell leukemia/lymphoma 2 family protein expression, increased calcium flux, and increased protein glycosylation [144].”

    From Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting (2023) · cites this paper as [144]

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Cited by

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  • Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting

    Henrot, P., Dupin, I., Schilfarth, P., Esteves, P., Blervaque, L., Zysman, M., Gouzi, F., Hayot, M., Pomiès, P., & Berger, P. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076454 · Cited by 85 · see citing works

    “Hyperammonemic stress is also known to be associated with COPD, and a recent study evidenced new pathways associated with hyperammonemia in skeletal muscle (in addition to the already-known mitochondrial dysfunction, oxidative stress, and senescence), such as antiapoptotic B-cell leukemia/lymphoma 2 family protein exp…”
    Background

Authors
Welch, N., Singh, S. S., Kumar, A., Dhruba, S. R., Mishra, S., Sekar, J., Bellar, A., Attaway, A. H., Chelluboyina, A., Willard, B. B., Li, L., Huo, Z., Karnik, S. S., Esser, K., Longworth, M. S., Shah, Y. M., Davuluri, G., Pal, R., & Dasarathy, S.
Affiliations
  • Cleveland Clinic (US)
  • Texas Tech University (US)
  • University of Florida (US)
  • University of Michigan (US)
  • Pennington Biomedical Research Center (US)
Corresponding author
  • Pal, Ranadip
  • Dasarathy, Srinivasan
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2021-09
Volume
297
Issue
3
Pages
101023
ISSN
0021-9258 (ISSN-L)
DOI
10.1016/j.jbc.2021.101023
PMC
PMC8424232
OpenAlex
W3189809100
Cited by
17
References
5
Citations by year
2026: 1 · 2025: 3 · 2024: 3 · 2023: 7 · 2022: 2 · 2021: 1
FWCI
1.02
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • ThinkTech (Texas Tech University) (submittedVersion, cc-by-nc-nd)
Funders
  • National Institutes of Health (1S10OD023436-01, 3U01AA026976 - 03S1, 5U01 DK062470-17S2, RO1 GM119174, P50 AA024333, R21 AR 071046, R56HL141744, RO1 AA021890, RO1 DK113196, UO1 AA 026976, UO1 DK061732)
  • U.S. Department of Defense
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
hyperammonemia, skeletal muscle, myotubes, ammonia metabolism, chromatin accessibility, mitochondrial dysfunction, oxidative stress, cellular senescence, Bcl-2 family proteins, calcium flux, protein glycosylation, liver cirrhosis, cellular stress response, multi-omics integration
MeSH terms
Animals, Flow Cytometry, Humans, Immunoblotting, Reproducibility of Results, Muscle, Skeletal, Muscle Fibers, Skeletal, Hyperammonemia, Genomics, Proteomics, Mice, Transcriptome, Real-Time Polymerase Chain Reaction

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