Trichostatin A regulates fibro/adipogenic progenitor adipogenesis epigenetically and reduces rotator cuff muscle fatty infiltration

Liu, Xuhui; Liu, Mengyao; Lee, Lawrence; Davies, M.R.Q.; Wang, Zili; Kim, Hubert

doi:10.1002/jor.24865

Cited by 19 publications

(22 citation statements)

References 49 publications

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“…The fibrosis and fat indices were quantified using ImageJ (NIH) by dividing the amount of collagen or lipids identified on Trichrome or Oil-red-O, respectively, by the total tissue section area (n = 3 to 4 mice/group/timepoint), as previously described [13] , [14] . Muscle fiber cross sectional area (CSA) was quantified using ImageJ (n = 3/group).…”

Section: Methodsmentioning

confidence: 99%

“…At 6 and 15 weeks, muscle segments from bilateral proximal and distal muscle samples relative to disc injury were pooled (6 weeks: n = 4; 15 weeks n = 3) for flow cytometry isolation of Sca1 + /PDGFRα + /CD31 − /CD45 − /integrin α7 − FAPs as previously described [14] .…”

Section: Methodsmentioning

confidence: 99%

“…The lumbar paraspinal muscles are likely an important, but less studied factor of this pathologic process, as they serve a crucial role in vertebral segmental stability as well as global function [6][7][8] . Previous large animal studies have demonstrated that disc disruption results in local-substances such as beta-3 adrenergic agonists and histone deacetylase inhibitors [13][14] , however their regenerative potential has yet to be characterized in the lumbar multifidus.…”

Section: Introductionmentioning

confidence: 99%

“…These pathologic changes in human muscle samples have been found to correlate with an increase in fibroadipogenic progenitor (FAP) stem cells in injured muscle, as well as increased fibrotic and adipogenic gene expression among this resident muscle stem cell population [12] . FAPs have also been shown to possess latent regenerative potential when exposed to certain pharmacologic substances such as beta-3 adrenergic agonists and histone deacetylase inhibitors [13] , [14] , however their regenerative potential has yet to be characterized in the lumbar multifidus.…”

Section: Introductionmentioning

confidence: 99%

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Paraspinal muscle degeneration and regenerative potential in a Murine model of Lumbar Disc Injury

Davies¹,

Kaur²,

Liu

et al. 2021

North American Spine Society Journal (NASSJ)

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Background Context: The association between low back pain and lumbar disc degeneration is not fully characterized. One potentially overlooked factor of this process is the lumbar multifidus, which plays a role in segmental stabilization and locomotion. Previous reports have shown multifidus degeneration to be associated with disc degeneration. The goal of this study was to develop a mouse model of advanced lumbar disc degeneration to recapitulate the pathology of the human multifidus in patients with lumbar disc degeneration and low back pain.Methods: C57BL/6 mice underwent a left anterolateral approach to the lumbar spine and disc puncture with a micro scalpel at L5/6 and L6/S1. Mice underwent behavioral analysis and functional gait testing. A subset of mice underwent 14T T2-weighted MRI to assess disc degeneration and paraspinal muscle quality. At 6 and 15 weeks, mice were sacrificed, and the multifidus muscles were harvested and divided into proximal and distal segments relative to disc injury. Histological analysis was performed to assess muscle degeneration, fiber type, and macrophage density. Fibroadipogenic progenitors (FAPs) were isolated for gene expression analysis with qPCR.Results: MRI demonstrated decreased intervertebral disc signal and paraspinal muscle atrophy at 6 weeks, with progressive degeneration and atrophy at 15 weeks. Disc injury resulted in delayed functional recovery and impaired gait. Histology demonstrated progressive multifidus fibrofatty degeneration between 6 and 15 weeks. CD68 + macrophage density was increased at 6 weeks but not 15 weeks. FAPs exhibited increased fibrotic and adipogenic gene expression at 6 weeks compared to sham with less of a difference in gene expression by 15 weeks. Conclusions:We have developed a mouse model of disc injury-mediated paraspinal muscle degeneration that recapitulates features of degenerative muscle pathology observed in patients with lumbar disc degeneration, and highlights the role of FAPs in mediating fibrofatty muscle degeneration after disc injury.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Paraspinal muscle degeneration and regenerative potential in a Murine model of Lumbar Disc Injury

Davies¹,

Kaur²,

Liu

et al. 2021

North American Spine Society Journal (NASSJ)

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“…The authors explain that the functional purpose of FAPs is still under intense investigation; however, their presence in skeletal muscle pathology may indicate the presence of a resident stem cell population that could aid in muscle regeneration under the proper stimulus. One study found that HDACi treatment in a murine RCT model reduced FAP fibro-adipogenic activity while promoting differentiation into brown/beige adipose tissue (BAT), a metabolically active alternative to energy-storing white adipose tissue (62).…”

Section: Beige Adipose Tissue: a Latent Regenerative Phenotype Of Fapsmentioning

confidence: 99%

Fibro-adipogenesis in Injured Rotator Cuff Muscle

Subhash

Davies

Gatto

et al. 2022

Curr. Tissue Microenviron. Rep.

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Purpose of Review Fibro-adipogenic progenitors were first characterized in 2010 and later found to contribute significantly to muscle regeneration and mediate degenerative changes in muscle following injury. These progenitors were also found to have an influence on the rotator cuff muscle’s response to chronic injury which is defined by fibrosis accompanied by massive fatty degeneration. The purpose of this review is to highlight progenitor cells, their contribution to fibro-adipogenesis in rotator cuff tissue, and the factors influencing fibro-adipogenesis in this tissue. Recent Findings Fibro-adipogenic progenitors are a key mediator of the fatty infiltration notably prevalent in rotator cuff injury. Relative to other muscle groups, the rotator cuff has relatively high rates of fibro-adipogenesis following massive chronic rotator cuff tears. This may be linked to the pre-injury density of fibro-adipogenic progenitors in muscle tissue affecting post-injury levels of fibro-adipogenesis. In addition, suprascapular nerve injury in rat models of rotator cuff tears has demonstrated worse, histologic, and biomechanical properties and lower healing rates of rotator cuff repairs. However, fatty infiltration in the rotator cuff following suprascapular nerve compression has been shown to be reversible following release of the nerve compression. Summary The fibro-adipogenic response to acute and chronic injury in rotator cuff tissue is determined by a complex array of factors including progenitor cell influence, transcriptional pathways, chronicity of the injury, anatomic location of injury, microenvironmental influences, and the severity of nerve involvement. Elucidating the complex interactions of these factors will provide potential targets for therapeutic intervention in vivo.

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Age‐dependent decline of B3AR agonist‐mediated activation of FAP UCP‐1 expression in murine models of chronic rotator cuff repair

Diaz,

Sang,

Garcia

et al. 2024

Journal Orthopaedic Research

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Amibegron, a β3‐adrenergic receptor (B3AR) agonist, has recently been shown to provide therapeutic effects for chronic rotator cuff (RC) tears by inducing the expression of uncoupling protein 1 (UCP‐1), a marker of brown fat, in fibroadipogenic progenitors (FAPs). However, it remains to be seen if these beneficial effects hold true with age and in older, more clinically relevant populations. This study seeks to understand the impacts of aging on the efficacy of amibegron to treat chronic RC tears. Young (4‐month‐old) and aged (33‐month‐old) C57BL/6 mice underwent a RC injury procedure with delayed repair (DR). Mice were equally randomized to receive amibegron or dimethyl sulfoxide (DMSO) treatments after repair. Functional ability was measured at baseline and 6‐weeks after DR. Wet muscle weight and histology of injured and contralateral supraspinatus were also analyzed 6‐weeks post‐DR. For in vitro histology and real‐time quantitative PCR experiments, FAPs were isolated from young and aged mice via fluorescence‐activated cell sorting. Young and aged FAPs were treated with amibegron or DMSO either immediately after seeding (early exposure) or 8‐days after seeding (late exposure). In vitro results showed that amibegron‐mediated FAP UCP‐1 expression decreases with age. In vivo data demonstrated that aged mice have a decreased responsiveness to amibegron and decreased propensity for intramuscular FAP UCP‐1 expression. Further, delayed amibegron treatment with RC repair did not lead to improvements in muscle atrophy and functional outcomes. Our findings demonstrate that age and the timing of interventions play a critical role in FAP‐targeted therapeutics for chronic injuries.

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Trichostatin A regulates fibro/adipogenic progenitor adipogenesis epigenetically and reduces rotator cuff muscle fatty infiltration

Cited by 19 publications

References 49 publications

Paraspinal muscle degeneration and regenerative potential in a Murine model of Lumbar Disc Injury

Paraspinal muscle degeneration and regenerative potential in a Murine model of Lumbar Disc Injury

Fibro-adipogenesis in Injured Rotator Cuff Muscle

Age‐dependent decline of B3AR agonist‐mediated activation of FAP UCP‐1 expression in murine models of chronic rotator cuff repair

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