Comprehensive Proteomic and Metabolomic Profiling of Soleus Muscle of Rats Exposed to Hindlimb Unloading Reveals Changes Related to Muscle Atrophy

Abstract Background Skeletal muscle atrophy, which is induced by factors such as disuse, spaceflight, certain medications, neurological disorders and malnutrition, is a global health issue with clinical manifestations mainly being a reduction in muscle mass and muscle weakness. Currently there is a lack of effective treatment for muscle atrophy. Hindlimb unloading is currently a commonly used model for muscle atrophy. However, the underlying mechanism of muscle atrophy induced by hindlimb unloading remains unclear, particular from the perspective of myocyte proteome and metabolism. Methods We first conducted proteomic sequencing based on mass spectrometry to explore the protein abundance changes of soleus muscles from rats exposed to hindlimb unloading. Then untargeted metabolomics analysis was performed, followed by the combined analysis of proteomic and metabolomic profiles. Results In our study, 1052 differentially expressed proteins and 377 differentially abundant metabolites were revealed in HU group compared to CON group. These differentially expressed proteins included some proteins which are mainly expressed in the fast-twitch muscle such as ACTN3, MYH4, MYBPC2 and MYOZ1. Some metabolism-related proteins such as GLUL, GSTM4 and NDUFS4 were screened out. Some differentially abundant metabolites including arachidylcarnitine and 7,8-dihydrobiopterin, along with pathways such as histidine metabolism, taurine and hypotaurine metabolism might be related to muscle atrophy. Protein and metabolism joint analysis revealed that some pathways such as glutathione metabolism, ferroptosis and lysosome pathways were likely to be involved in soleus atrophy. Conclusion In this study, we have applied integrated deep proteomic and metabolomic analysis. The upregulation of proteins which are expressed in fast-twitch fibers indicated the conversion of slow-twitch fibers to fast-twitch fibers under HU. Some metabolism-related proteins have been screened out. Besides, some differentially abundant metabolites and pathways revealed the important role of metabolism in the muscle atrophy of soleus. Our study provides insights into the pathogenesis and treatment of muscle atrophy that results from unloading by integrating the proteomics and metabolomics of soleus muscles.