Adipogenic and myogenic gene expression in rotator cuff muscle of the sheep after tendon tear

Abstract

Chronic rotator cuff tendon tears lead to fatty infiltration and muscle atrophy with impaired physiological functions of the affected muscles. However, the cellular and molecular mechanisms of corresponding pathophysiological processes remain unknown. The purpose of this study was to characterize the expression pattern of adipogenic (PPARg, C/EBPb) and myogenic (myostatin, myogenin, Myf-5) transcription factors in infraspinatus muscle of sheep after tenotomy, implantation of a tension device, refixation of the tendon, and rehabilitation, reflecting a model of chronic rotator cuff tears. In contrast to human patients, the presented sheep model allows a temporal evaluation of the expression of a given marker in the same individual over time. Semiquantitative RT/PCR analysis of PPARgã , myostatin, myogenin, Myf-5, and C/EBPb transcript levels was carried out with sheep muscle biopsy-derived total RNA. We found a significantly increased expression of Myf-5 and PPARg after tenotomy and a significant change for Myf-5 and C/EBPb after continuous traction and refixation. This experimental sheep model allows the molecular analysis of pathomechanisms of muscular changes after rotator cuff tear. The results point to a crucial role of the transcription factors PPARg, C/EBPb, and Myf-5 in impairment and regeneration of rotator cuff muscles after tendon tears in sheep. ß

Fatty acid‐binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia‐inducible factor 1 in mice

“…Adipogenic transcription factors have been considered key regulators for fatty degeneration of muscle after RCT. One research group reported that the transcription factors PPARγ, C/EBPβ, and Myf‐5 play crucial roles in impairment and regeneration of rotator cuff muscles after tendon tears in a sheep model 8. Joshi et al suggested that mammalian target of rapamycin signaling plays an important role in muscle atrophy after massive RCTs in a rat model and mediates rotator cuff fatty infiltration via SREBP‐1 and PPARγ 23.…”

“…Therefore, RCT could be considered a good model to understand age‐associated muscle fatty infiltration. To date, the mechanism of muscle fatty infiltration in RCT has been investigated using various animal models 8, 9, 10, 11, 12, 13. However, the molecular mechanisms underlying rotator cuff muscle atrophy and fatty infiltration remain largely unknown.…”

“…Although the factors leading to fat accumulation in the muscle are not yet fully defined, it has been reported that aging, muscle injury, mechanical unloading, and hormonal imbalance are main causes of ectopic fat formation 1, 2, 18, 19, 20. With respect to the molecular mechanism underlying muscle fat accumulation, it has been reported that pluripotent stem cells or progenitor cells residing in the muscle differentiate into adipocytes by the action of adipogenic transcription factors such as CCAAT/enhancer binding protein alpha (C/EBPα) and peroxisome proliferator activated receptor gamma (PPARγ) 8, 21, 22. Previous studies have suggested that rotator cuff fatty infiltration is also mediated by these adipogenic transcription factors 8, 23, 24, 25.…”

“…With respect to the molecular mechanism underlying muscle fat accumulation, it has been reported that pluripotent stem cells or progenitor cells residing in the muscle differentiate into adipocytes by the action of adipogenic transcription factors such as CCAAT/enhancer binding protein alpha (C/EBPα) and peroxisome proliferator activated receptor gamma (PPARγ) 8, 21, 22. Previous studies have suggested that rotator cuff fatty infiltration is also mediated by these adipogenic transcription factors 8, 23, 24, 25. However, considering the population of stem cells available at old age, it is possible that other regulators are also involved in intramuscular fat accumulation.…”

Molecular mechanism of fatty degeneration in rotator cuff muscle with tendon rupture

“…8,9 CCAAT/ enhancer-binding proteins (C/EBPs) and the peroxisome proliferator-activated receptors (PPARs), members of two families of transcription factors, have been implicated in the differentiation of preadipocytes into mature adipocytes. 10 Frey et al 11 reported an upregulation of adipogenic transcription factors after experimental chronic rotator cuff tear. However, in the rotator cuff muscles, the molecular mechanism of the differentiation of muscle progenitors into adipocytes has not been fully clarified yet.…”