Simvastatin Reduces Fibrosis and Protects Against Muscle Weakness after Massive Rotator Cuff Tear

Davis, M. Edward; Gumucio, Jonathan P.; Korn, Michael A.; Mendias, Christopher L.; Bedi, Asheesh

doi:10.1016/j.jse.2014.11.006

Cited by 19 publications

(28 citation statements)

References 12 publications

(13 reference statements)

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“…In addition to muscle atrophy, fibrosis is a common feature of rotator cuff tears (49)(50)(51). In the current study, 10 d after injury, there was an increase in the levels of the fibroblast marker S100A4 and several proteoglycans including lumican, osteoglycin, periostin, prolargin, thrombospondin 4, and vinculin.…”

Section: Discussionsupporting

confidence: 52%

Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

et al. 2019

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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 of rotator cuff injury in this study because 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 d 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.—Gumucio, J. P., Qasawa, A. H., Ferrara, P. J., Malik, A. N., Funai, K., McDonagh, B., Mendias, C. L. Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis. FASEB J. 33, 7863–7881 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 52%

Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

et al. 2019

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“…4 The findings of reduced force production are consistent with the observed general reduction in contractile and muscle fiber cytoskeletal genes and alterations in muscle regenerative genes in this study, and in previous reports evaluating pathological changes in muscles after rotator cuff tear. 20,25,[36][37][38] Fibrosis is commonly observed after rotator cuff tear. 25,37,38 In the current study, there was a general upregulation in type I (Col1a1 and Col1a2) and type IV (Col4a1) collagen, elastin (Eln), as well as the proteoglycans biglycan (Bgn), thrombospondin 4 (Thsb4), tenomodulin (Tnmd), and tenascin C (Tnc) after injury.…”

Section: Discussionmentioning

confidence: 99%

“…20,25,[36][37][38] Fibrosis is commonly observed after rotator cuff tear. 25,37,38 In the current study, there was a general upregulation in type I (Col1a1 and Col1a2) and type IV (Col4a1) collagen, elastin (Eln), as well as the proteoglycans biglycan (Bgn), thrombospondin 4 (Thsb4), tenomodulin (Tnmd), and tenascin C (Tnc) after injury. Fibroblasts synthesize and remodel the muscle ECM, 39 and fibroblasts markers such as S100a4, Scx, and Tcf7l2 were upregulated and not different between B6 and MRL mice after injury.…”

Section: Discussionmentioning

confidence: 99%

“…Permeabilized muscle fiber contractility was performed as described. 20,25 Small bundles of fibers were dissected free of the muscle, chemically permeabilized, and stored at −80°C. Individual fibers were placed in a chamber containing relaxing solution and secured at one end to a servomotor (Aurora Scientific, Aurora, ON) and the other end to a force transducer (Aurora Scientific) using 10-0 monofilament nylon suture.…”

Section: Muscle Fiber Contractilitymentioning

confidence: 99%

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The MRL/MpJ Mouse Strain Is Not Protected From Muscle Atrophy and Weakness After Rotator Cuff Tear

Talarek

Piacentini

Konja

et al. 2019

Journal Orthopaedic Research

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Chronic rotator cuff tears are a common source of shoulder pain and disability. Patients with rotator cuff tears often have substantial weakness, fibrosis, and fat accumulation, which limit successful surgical repair and postoperative rehabilitation. The Murphy Roths Large (MRL) strain of mice have demonstrated superior healing and protection against pathological changes in several disease and injury conditions. We tested the hypothesis that, compared with the commonly used C57Bl/6 (B6) strain, MRL mice would have less muscle fiber atrophy and fat accumulation, and be protected against the loss in force production that occurs after cuff tear. Adult male B6 and MRL mice were subjected to a rotator cuff tear, and changes in muscle fiber contractility and histology were measured. RNA sequencing and shotgun metabolomics and lipidomics were also performed. The muscles were harvested one month after tear. B6 and MRL mice had a 40% reduction in relative muscle force production after rotator cuff tear. RNA sequencing identified an increase in fibrosis‐associated genes and a reduction in mitochondrial metabolism genes. The markers of glycolytic metabolism increased in B6 mice, while MRL mice appeared to increase amino acid metabolism after tear. There was an accumulation of lipid after injury, although there was a divergent response between B6 and MRL mice in the types of lipid species that accrued. There were strain‐specific differences between the transcriptome, metabolome, and lipidome of B6 and MRL mice, but these differences did not protect MRL mice from weakness and pathological changes after rotator cuff tear. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:811‐822, 2020

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“…Permeabilized muscle fiber contractility was performed as modified from previous publications 16,21 . Small bundles of muscle fibers were dissected free of the muscle, chemically permeabilized, and stored at -80ºC.…”

Section: Muscle Fiber Contractilitymentioning

confidence: 99%

The MRL/MpJ Mouse Strain Is Not Protected From Muscle Atrophy And Weakness After Rotator Cuff Tear

Talarek

Piacentini

Konja

et al. 2019

Preprint

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Chronic rotator cuff tears are a common source of shoulder pain and disability. Patients with rotator cuff tears often have substantial weakness, fibrosis, and fat accumulation which limit successful surgical repair and postoperative rehabilitation. The Murphy Roths Large (MRL) strain of mice have demonstrated superior healing and protection against pathological changes in several disease and injury conditions. We tested the hypothesis that, compared to the commonly used C57Bl/6 (B6) strain, MRL mice would have less muscle fiber atrophy and fat accumulation, and be protected against the loss in force production that occurs after cuff tear. Adult male mice B6 and MRL mice were subjected to a rotator cuff tear, and changes in muscle fiber contractility and histology were measured. RNA sequencing, and shotgun metabolomics and lipidomics were also performed. Muscles were harvested one month after tear. B6 and MRL mice had a 40% reduction in relative muscle force production after rotator cuff tear. RNA sequencing identified an increase in fibrosis-associated genes and a reduction in mitochondrial metabolism genes.Markers of glycolytic metabolism increased in B6 mice, while MRL mice appeared to increase amino acid metabolism after tear. There was an accumulation of lipid after injury, although there was a divergent response between B6 and MRL mice in the types of lipid species that accrued.There were strain-specific differences between the transcriptome, metabolome, and lipidome of B6 and MRL mice, but these differences did not protect MRL mice from weakness and pathological changes after rotator cuff tear.

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Simvastatin Reduces Fibrosis and Protects Against Muscle Weakness after Massive Rotator Cuff Tear

Cited by 19 publications

References 12 publications

Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

The MRL/MpJ Mouse Strain Is Not Protected From Muscle Atrophy and Weakness After Rotator Cuff Tear

The MRL/MpJ Mouse Strain Is Not Protected From Muscle Atrophy And Weakness After Rotator Cuff Tear

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