Shared and unique phosphoproteomics responses in skeletal muscle from exercise models and in hyperammonemic myotubes
Nicole Welch,
Shashi Shekhar Singh,
Ryan Musich,
M. Shahid Mansuri,
Annette Bellar,
Saurabh Mishra,
Aruna K. Chelluboyina,
Jinendiran Sekar,
Amy H. Attaway,
Ling Li,
Belinda Willard,
Troy A. Hornberger,
Srinivasan Dasarathy
Affiliations
Nicole Welch
Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44195, USA
Shashi Shekhar Singh
Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH 44195, USA
Ryan Musich
Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH 44195, USA
M. Shahid Mansuri
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA
Annette Bellar
Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH 44195, USA
Saurabh Mishra
Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH 44195, USA
Aruna K. Chelluboyina
Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH 44195, USA
Jinendiran Sekar
Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH 44195, USA
Amy H. Attaway
Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH 44195, USA
Ling Li
Proteomics Core, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, USA
Belinda Willard
Proteomics Core, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, USA
Troy A. Hornberger
Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, USA
Srinivasan Dasarathy
Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44195, USA; Corresponding author
Summary: Skeletal muscle generation of ammonia, an endogenous cytotoxin, is increased during exercise. Perturbations in ammonia metabolism consistently occur in chronic diseases, and may blunt beneficial skeletal muscle molecular responses and protein homeostasis with exercise. Phosphorylation of skeletal muscle proteins mediates cellular signaling responses to hyperammonemia and exercise. Comparative bioinformatics and machine learning-based analyses of published and experimentally derived phosphoproteomics data identified differentially expressed phosphoproteins that were unique and shared between hyperammonemic murine myotubes and skeletal muscle from exercise models. Enriched processes identified in both hyperammonemic myotubes and muscle from exercise models with selected experimental validation included protein kinase A (PKA), calcium signaling, mitogen-activated protein kinase (MAPK) signaling, and protein homeostasis. Our approach of feature extraction from comparative untargeted “omics” data allows for selection of preclinical models that recapitulate specific human exercise responses and potentially optimize functional capacity and skeletal muscle protein homeostasis with exercise in chronic diseases.
