Identification of lipid droplet-associated proteins in the formation of macrophage-derived foam cells using microarrays

Flood

Harning

et al. 2014

Bone & Joint Research

Objectives Rotator cuff tears are among the most common and debilitating upper extremity injuries. Chronic cuff tears result in atrophy and an infiltration of fat into the muscle, a condition commonly referred to as ‘fatty degeneration’. While stem cell therapies hold promise for the treatment of cuff tears, a suitable immunodeficient animal model that could be used to study human or other xenograft-based therapies for the treatment of rotator cuff injuries had not previously been identified.Methods A full-thickness, massive supraspinatus and infraspinatus tear was induced in adult T-cell deficient rats. We hypothesised that, compared with controls, 28 days after inducing a tear we would observe a decrease in muscle force production, an accumulation of type IIB fibres, and an upregulation in the expression of genes involved with muscle atrophy, fibrosis and inflammation.Results Chronic cuff tears in nude rats resulted in a 30% to 40% decrease in muscle mass, a 23% reduction in production of muscle force, and an induction of genes that regulate atrophy, fibrosis, lipid accumulation, inflammation and macrophage recruitment. Marked large lipid droplet accumulation was also present.Conclusions The extent of degenerative changes in nude rats was similar to what was observed in T-cell competent rats. T cells may not play an important role in regulating muscle degeneration following chronic muscle unloading. The general similarities between nude and T-cell competent rats suggest the nude rat is likely an appropriate preclinical model for the study of xenografts that have the potential to enhance the treatment of chronically torn rotator cuff muscles.Cite this article: Bone Joint Res 2014;3:262–72.

Section: Discussionsupporting

confidence: 39%

T lymphocytes are not required for the development of fatty degeneration after rotator cuff tear

Flood

Harning

et al. 2014

Bone & Joint Research

“…In atherosclerosis, a population of fatty macrophages, often referred to as “foam cells”, uptake high levels of lipid and promote local tissue inflammation 7 . Activation of the transcription factor PPAR-γ plays an important role in the differentiation of fatty macrophages, which upon differentiation express high levels of Apolipoprotein E (ApoE) and FSP27 at high levels 24; 48 . In the current study, substantial elevations in PPAR-γ, ApoE and FSP27 were observed.…”

Section: Discussionmentioning

confidence: 99%

Aging-associated exacerbation in fatty degeneration and infiltration after rotator cuff tear

Journal of Shoulder and Elbow Surgery

Korn

Saripalli

et al. 2014

104

Background Rotator cuff tears are one of the most common musculoskeletal complaints and a substantial source of morbidity in elderly patients. Chronic cuff tears are associated with muscle atrophy and an infiltration of fat to the area, a condition known as “fatty degeneration.” To improve the treatment of cuff tears in elderly patients, a greater understanding of the changes in the contractile properties of muscle fibers and the molecular regulation of fatty degeneration is essential. Methods Using a full-thickness, massive supraspinatus and infraspinatus tear model in elderly rats, we measured fiber contractility and determined changes in fiber type distribution that develop 30 days after 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 muscle fibers, an accumulation of type IIb fibers, and an upregulation in atrophic, fibrogenic, and inflammatory gene expression would occur in torn cuff muscles. Results Thirty days following tear, we observed a reduction in muscle fiber force and an induction of RNA molecules that regulate atrophy, fibrosis, lipid accumulation, inflammation and macrophage recruitment. A marked accumulation of advanced glycation end products, and a significant accretion of macrophages in areas of fat accumulation were observed. Conclusions The extent of degenerative changes in old rats was greater than that observed in adults. Additionally, we identified that the ectopic fat accumulation that occurs in chronic cuff tears does not occur by activation of canonical intramyocellular lipid storage and synthesis pathways.

“…In fatty atherosclerotic plaques, macrophages differentiate into a “foam cell” phenotype and serve as the core cellular component of the plaque (47). Once they have differentiated into foam cells, they express Apolipoprotein E (ApoE) and CIDEC at high levels (58). ApoE is a central component of very-low density lipoproteins and chylomicron particles (58), and CIDEC plays an important role in lipid droplet formation and fat metabolism (59).…”

Section: Discussionmentioning

confidence: 99%

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

Journal Orthopaedic Research

Davis

Bradley

et al. 2012

159

Summary 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, 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.