The effect of tear size and nerve injury on rotator cuff muscle fatty degeneration in a rodent animal model

Abstract

Background Irreversible muscle changes following rotator cuff tears is a well-known negative prognostic factor after shoulder surgery. Currently, little is known about the pathomechanism of fatty degeneration of the rotator cuff muscles after chronic cuff tears. Hypothesis/Purpose The purposes of this study were: 1) to develop a rodent animal model of chronic rotator cuff tears that can reproduce fatty degeneration of the cuff muscles seen clinically, 2) to describe the effects of tear size and concomitant nerve injury on muscle degeneration, and 3) to evaluate the changes in gene expression of relevant myogenic and adipogenic factors following rotator cuff tears using the animal model. Methods Rotator cuff tears were created in rodents with and without transection of the suprascapular nerve. The supraspinatus and infraspinatus muscles were examined 2, 8, and 16 weeks after injury for histological evidence of fatty degeneration and expression of myogenic and adipogenic genes. Results Histological analysis revealed adipocytes, intramuscular fat globules, and intramyocellular fat droplets in the tenotomized and neurotomized supraspinatus and infraspinatus muscles. Changes increased with time and were most severe in the muscles with combined tenotomy and neurotomy. Adipogenic and myogenic transcription factors and markers were upregulated in muscles treated with tenotomy or tenotomy combined with neurotomy compared to normal muscles. Conclusions The present study describes a rodent animal model that produces fatty degeneration of the rotator cuff muscles similar to human muscles after chronic cuff tears. The severity of changes was associated with tear size and concomitant nerve injury.

Muscle Gene Expression Patterns in Human Rotator Cuff Pathology

“…Although we are aware of no human rotator cuff data regarding gene expression markers of adipogenesis, some data are available in animals. These data suggest similar trends to those observed in our study, although the relative differences between injured and control animals were much smaller and appear to be related to the addition of neurotomy 38 . The family of genes related to fibrosis showed evidence of profibrotic activity in the tendinopathy group (COL3A1, TIMP1, and TIMP3).…”

“…This has been observed previously in human subjects with rotator cuff tears 35 , although the expression data presented here indicate a much greater ratio between muscles with a massive tear and less severe injury states as well as a more obvious effect when massive tears are compared with full-thickness tears. Similarly, upregulation of MSTN has been observed previously in animal models of rotator cuff injury, although the relative change compared with controls was extremely small 38 .…”

Mechanisms of fatty degeneration in massive rotator cuff tears

“…4 Recent rat models of massive RCTs have used a 5-mm tendon defect to successfully show muscle atrophy and fatty infiltration of the injured muscle. 32,33 Two studies in rats have shown that simultaneous suprascapular nerve injury and massive RCTs have significantly increased the amounts of fatty infiltration and muscle atrophy. 32,33 Interestingly, Rowshan et al 42 reported that isolated neurologic injury in rabbits produces fatty infiltration that is phenotypically comparable to that in those undergoing massive RCTs.…”

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

“…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.…”