PT  - JOURNAL ARTICLE
AU  - Gumucio, Jonathan P
AU  - Qasawa, Austin H
AU  - Ferrara, Patrick J
AU  - Malik, Afshan N
AU  - Funai, Katsuhiko
AU  - McDonagh, Brian
AU  - Mendias, Christopher L
TI  - Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis
AID  - 10.1101/471979
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 471979
4099  - http://biorxiv.org/content/early/2018/11/18/471979.short
4100  - http://biorxiv.org/content/early/2018/11/18/471979.full
AB  - Myosteatosis is the pathological accumulation of lipid that can occur in conjunction with atrophy and fibrosis following skeletal muscle injury. Little is known about the mechanisms by which lipid accumulates in myosteatosis, but many clinical studies have demonstrated the degree of lipid infiltration negatively correlates with muscle function and regeneration. Our objective was to determine the pathological changes that result in lipid accumulation in injured muscle fibers. We used a rat model of rotator cuff injury in this study, as the rotator cuff muscle group is particularly prone to the development of myosteatosis after injury. Muscles were collected from uninjured controls, or 10, 30, or 60 days after injury, and analyzed using a combination of muscle fiber contractility assessments, RNA sequencing, and undirected metabolomics, lipidomics and proteomics, along with bioinformatics techniques, to identify potential pathways and cellular processes that are dysregulated after rotator cuff tear. Bioinformatics analyses indicated that mitochondrial function was likely disrupted after injury. Based on these findings, and given the role that mitochondria play in lipid metabolism, we then performed targeted biochemical and imaging studies and determined that mitochondrial dysfunction and reduced fatty acid oxidation likely leads to the accumulation of lipid in myosteatosis.Non-Standard Abbreviations2PG+3PG2-phosphoglycerate and 3-phosphoglycerateADPadenosine diphosphateAMPadenosine monophosphateATPadenosine triphosphateCIT+ICITcitrate and isocitrateCMPcytidine monophosphateF6P+G6Pfructose-6-phosphate and glucose-6-phosphateFADflavin adenine dinucleotideGDPguanosine diphosphateGMPguanosine monophosphateNADnicotinamide adenine dinucleotideNADPnicotinamide adenine dinucleotide phosphateR5P+X5Pribulose 5-phosphate and xylulose 5-phosphateUDPuridine diphosphateUMPuridine monophosphateUTPuridine triphosphate