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Rotator cuff tear reduces muscle fiber specific force production and induces macrophage accumulation and autophagy.

ABSTRACT: Full-thickness tears to the rotator cuff can cause severe pain and disability. Untreated tears progress in size and are associated with muscle atrophy and an infiltration of fat to the area, a condition known as "fatty degeneration." To improve the treatment of rotator cuff tears, a greater understanding of the changes in the contractile properties of muscle fibers and the molecular regulation of fatty degeneration is essential. Using a rat model of rotator cuff injury, we measured the force generating capacity of individual muscle fibers and determined changes in muscle fiber type distribution that develop after a full thickness rotator cuff tear. We also measured the expression of mRNA and miRNA transcripts involved in muscle atrophy, lipid accumulation, and matrix synthesis. We hypothesized that a decrease in specific force of rotator cuff muscle fibers, an accumulation of type IIb fibers, and an upregulation in fibrogenic, adipogenic, and inflammatory gene expression occur in torn rotator cuff muscles. Thirty days following rotator cuff tear, we observed a reduction in muscle fiber force production, an induction of fibrogenic, adipogenic, and autophagocytic mRNA and miRNA molecules, and a dramatic accumulation of macrophages in areas of fat accumulation.

SUBMITTER: Gumucio JP

PROVIDER: S-EPMC3449033 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Rotator cuff tear reduces muscle fiber specific force production and induces macrophage accumulation and autophagy.

Gumucio Jonathan P JP Davis Max E ME Bradley Joshua R JR Stafford Patrick L PL Schiffman Corey J CJ Lynch Evan B EB Claflin Dennis R DR Bedi Asheesh A Mendias Christopher L CL

Journal of orthopaedic research : official publication of the Orthopaedic Research Society 20120613 12

Full-thickness tears to the rotator cuff can cause severe pain and disability. Untreated tears progress in size and are associated with muscle atrophy and an infiltration of fat to the area, a condition known as "fatty degeneration." To improve the treatment of rotator cuff tears, a greater understanding of the changes in the contractile properties of muscle fibers and the molecular regulation of fatty degeneration is essential. Using a rat model of rotator cuff injury, we measured the force gen ...[more]

PMID: 22696414

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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:Rotator cuff (RC) tears are prevalent in the population above the age of 60. The disease progression leads to muscle atrophy, fibrosis, and fatty infiltration in the chronic state, which is not improved with intervention or surgical repair. This highlights the need to better understand the underlying dysfunction in muscle after RC tendon tear. Contemporary studies aimed at understanding muscle pathobiology after RC tear have considered transcriptional data in mice, rats and sheep models at 2-3 time points (1 to 16 weeks post injury). However, none of these studies observed a transition or resurgence of gene expression after the initial acute time points. In this study, we collected rabbit supraspinatus muscle tissue with high temporal resolution (1, 2, 4, 8, and 16 weeks) post-tenotomy (n = 6/group), to determine if unique, time-dependent transcriptional changes occur. RNA sequencing and analyses were performed to identify a transcriptional timeline of RC muscle changes and related morphological sequelae. At 1-week post-tenotomy, the greatest number of differentially expressed genes was observed (1,069 up/873 down) which decreases through 2 (170/133), 4 (86/41), and 8 weeks (16/18), followed by a resurgence and transition of expression at 16 weeks (1,421/293), a behavior which previously has not been captured or reported. Broadly, 1-week post-tenotomy is an acute time point with expected immune system responses, catabolism, and changes in energy metabolism, which continues into 2 weeks with less intensity and greater contribution from mitochondrial effects. Expression shifts at 4 weeks post-tenotomy to fatty acid oxidation, lipolysis, and general upregulation of adipogenesis related genes. The effects of previous weeks' transcriptional dysfunction present themselves at 8 weeks post-tenotomy with enriched DNA damage binding, aggresome activity, extracellular matrix-receptor changes, and significant expression of genes known to induce apoptosis. At 16 weeks post-tenotomy, there is a range of enriched pathways including extracellular matrix constituent binding, mitophagy, neuronal activity, immune response, and more, highlighting the chaotic nature of this time point and possibility of a chronic classification. Transcriptional activity correlated significantly with histological changes and were enriched for biologically relevant pathways such as lipid metabolism. These data provide platform for understanding the biological mechanisms of chronic muscle degeneration after RC tears.

Project description:BackgroundThe upper normoglycemic range has been proposed as a risk factor for degenerative rotator cuff tendon tear (RCT), and insulin resistance has been suggested as a risk factor for tendinopathy. However, no research has established their association with degenerative RCT in the general population. This study aimed to determine whether fasting glucose levels and insulin resistance are risk factors for degenerative RCT in the normoglycemic population and identify the risk range for fasting glucose.MethodsThis study included 418 normoglycemic participants from a rural cohort. Participants completed questionnaires, physical exams, blood tests, and MRI evaluations of both shoulders. Insulin resistance was assessed using a triglyceride/high-density-lipoprotein (TG/HDL) ≥ 3.5. Logistic regression analysis was used to determine the association between fasting glucose level, TG/HDL ≥ 3.5, and other factors and degenerative RCT. The study calculated the areas under the receiver operating characteristic curve (AUC) to determine the more appropriate predicting value between the scale and categorical values of fasting glucose levels, and compared the AUCs using the DeLong method.ResultsIn the multivariable analyses, both scale and categorical values of fasting glucose levels, and TG/HDL ≥ 3.5 were significantly associated with degenerative RCT. Fasting glucose levels ≥ 90.5 mg/dL (OR: 3.87, 95% CI: 2.10-7.06) in scale value and 90-99 mg/dL (OR: 4.13, 95% CI: 2.87-8.12) in categorical value were significantly associated with degenerative RCT (P < .001). The AUC of the scale value of fasting glucose levels ≥ 90.5 mg/dL was 0.68. The AUC of the categorical value of fasting glucose levels of 90-99 mg/dL was 0.70. Because of the significantly larger AUC of the categorical value of fasting glucose levels of 90-99 mg/dL, those fasting glucose levels were determined to be independently associated with degenerative RCT (P < .001).ConclusionsHigh fasting glucose levels within the normal range may link to increase insulin resistance and risk of degenerative RCT. Normoglycemic levels of 90-99 mg/dL and insulin resistance may be risk factors for degenerative RCT.Level of evidenceLevel III, prognostic study.

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Rotator cuff tear reduces muscle fiber specific force production and induces macrophage accumulation and autophagy.

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Rotator cuff tear reduces muscle fiber specific force production and induces macrophage accumulation and autophagy.

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