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Defective Mitochondrial Lipid Oxidation Results in the Pathological Accumulation of Fat After Rotator Cuff Tear

ABSTRACT: Myosteatosis, also known as fatty infiltration, is the pathological accumulation of lipid that occurs in conjunction with atrophy and fibrosis following rotator cuff injury. Little is known about the mechanisms by which lipid accumulates in myosteatosis, but many studies have demonstrated the degree of lipid infiltration negatively correlates with muscle function and regeneration. Identifying how reduced mechanical loading activates molecular pathways that lead to myosteatosis could help to develop targeted therapies to improve functional outcomes after rotator cuff repair. Our objective was to use cutting compare muscle fiber contracility, proteomic, RNA sequencing and shotgun metabolomics along with bioinformatics to identify potential pathways and cellular processes that are dysregulated after rotator cuff teaar.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Skeletal Muscle

DISEASE(S): Wounds And Injuries

SUBMITTER: Brian McDonagh

LAB HEAD: Brian McDonagh

PROVIDER: PXD009034 | Pride | 2020-04-15

REPOSITORIES: Pride

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Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis.

Gumucio Jonathan P JP Qasawa Austin H AH Ferrara Patrick J PJ Malik Afshan N AN Funai Katsuhiko K McDonagh Brian B Mendias Christopher L CL

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20190402 7

Myosteatosis is the pathologic 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 that the degree of lipid infiltration negatively correlates with muscle function and regeneration. Our objective was to determine the pathologic changes that result in lipid accumulation in injured muscle fibers. We used a rat model ...[more]

PMID: 30939247

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Project description:Myosteatosis is the pathological accumulation of lipid that occurs in conjunction with atrophy and fibrosis following skeletal muscle injury or disease. Little is known about the mechanisms by which lipid accumulates in myosteatosis, but many studies have demonstrated the degree of lipid infiltration negatively correlates with muscle function and regeneration. Our goal was to identify biochemical pathways that lead to muscle dysfunction and lipid accumulation in injured rotator cuff muscles, a model that demonstrates severe myosteatosis. Adult rats were subjected to a massive tear to the rotator cuff musculature. After a period of either 0 (healthy control), 10, 30, or 60 days, muscles were prepared for RNA sequencing, shotgun lipidomics, metabolomics, biochemical measures, electron microscopy, and muscle fiber contractility. Following rotator cuff injury, there was a decrease in muscle fiber specific force production that was lowest at 30d. There was a dramatic time dependent increase in triacylglyceride content. Interestingly, genes related to not only triacylglyceride synthesis, but also lipid oxidation were largely downregulated over time. Using bioinformatics techniques, we identified that biochemical pathways related to mitochondrial dysfunction and reactive oxygen species were considerably increased in muscles with myosteatosis. Long chain acyl-carnitines and L-carnitine, precursors to beta-oxidation, were depleted following rotator cuff tear. Electron micrographs showed injured muscles displayed large lipid droplets within mitochondria at early time points, and an accumulation of peripheral segment mitochondria at all time points. Several markers of oxidative stress were elevated following rotator cuff tear. The results from this study suggest that the accumulation of lipid in myosteatosis is not a result of canonical lipid synthesis, but occurs due to decreased lipid oxidation in mitochondria. A failure in lipid utilization by mitochondria would ultimately cause an accumulation of lipid even in the absence of increased synthesis. Further study will identify whether this process is required for the onset of myosteatosis.

Project description:This data set was downloaded from MetaboLights (http://www.ebi.ac.uk/metabolights/) accession number MTBLS322 Abstract:Reversal of fatty infiltration of pennate rotator cuff muscle after tendon release is hitherto impossible. The administration of nandrolone starting at the time of tendon release prevents the increase in fat content, but does not revert established fatty infiltration. We hypothesised that tendon release and myotendinous retraction cause alterations in lipid related gene expression leading to fatty muscle infiltration, which can be suppressed by nandrolone through its genomic actions if applied immediately after tendon release. The effects of infraspinatus tendon release and subsequent tendon repair at 16 weeks were studied in six Swiss Alpine sheep. In the interventional groups, 150mg nandrolone was administered weekly after tendon release until sacrifice (N22W, n=6) or starting at the time of repair (N6W, n=6). Infraspinatus volume, composition, expressed transcripts, lipids, and selected proteins were analyzed at baseline, 16 and 22 weeks. Tendon release reduced infraspinatus volume by 22% and increased fat content from 11% to 38%. These changes were not affected by repair. Fatty infiltration was associated with up-regulation of 227 lipid species, and increased levels of the adipocyte differentiation marker PPARG2 (peroxisome proliferator-activated receptor gamma 2). Nandrolone abrogated lipid accumulation, halved the loss in fiber area percentage, and up-regulated androgen receptor levels and transcript expression in the N22W but not the N6W group. The results document that nandrolone mitigates muscle-to-fat transformation after tendon release via a general down-regulation of lipid accumulation concomitantly with up-regulated expression of its nuclear receptor and downstream transcripts in skeletal muscle. Reduced responsiveness of retracted muscle to nandrolone as observed in the N6W group is reflected by a down-regulated transcript response.

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