Integrated multiomics analysis identifies molecular landscape perturbations during hyperammonemia in skeletal muscle and myotubes

• DOI: 10.1016/j.jbc.2021.101023
• Publication Date: 2021-07-31T14:49:31Z
• Authors: Nicole Welch; Shashi Shekhar Singh; Avinash Kumar; Saugato Rahman Dh...; Saurabh Mishra; Jinendiran Sekar; Annette Bellar; Amy H. Attaway; Aruna Chelluboyina; Belinda B. Willard; Ling Li; Zhiguang Huo; Sadashiva S. Karnik; Karyn Esser; Michelle S. Longw...; Yatrik M. Shah; Gangarao Davuluri; Ranadip Pal; Srinivasan Dasarathy
• Keywords: Hyperammonemia

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