Aged Mice Demonstrate Greater Muscle Degeneration of Chronically Injured Rotator Cuff

Abstract

Massive tears of the rotator cuff (RC) are often associated with progressive and irreversible muscle degeneration due to fibrosis, fatty infiltration, and muscle atrophy. RC tears are common in individuals older than 60 years and the repair of these tears is amongst the most prevalent of orthopedic procedures. However, most current models of this injury are established in young animals, which may not accurately recapitulate the clinical condition. In this study, we used a murine model of massive RC tears to evaluate agerelated muscle degeneration following chronic injury. The expression of the fibro-adipogenic genes encoding collagen type III and leptin was higher in aged RC compared with matched injured young tissue at 2 weeks post-injury, and development of fibrosis was accelerated in aged mice within 5 days post-injury. Furthermore, the synthesis of collagens type I and III and fat tissue accumulation were significantly higher in injured RCs of aged mice. Similar frequency of fibro-adipogenic PDGFRβ + PDGFRα + progenitor cells was measured in noninjured RC of aged and young mice, but PDGFRβ + PDGFRα + cells contributed to significantly larger fibrotic lesions in aged RCs within 2 weeks post-injury, implying a more robust fibrotic environment in the aged injured muscle. Altogether, these findings demonstrate agedependent differences in RC response to chronic injury with a more profound fibro-adipogenic change in aged muscles. Clinically, cell therapies for muscular pathologies should not only consider the cell type being transplanted but also the recipient milieu into which these cells are seeded.

MicroRNA-29a Mitigates Subacromial Bursa Fibrosis in Rotator Cuff Lesion with Shoulder Stiffness

“…Experimental analyses of this study were in agreement with other studies reporting that miR-29a reduces fibrotic responses in pulmonary sclerosis, [17], toxin-mediated liver injury [18], osteoarthritic synovitis [19], and diabetic kidneys [21], etc. COL3A1 is an important hallmark of fibrosis in chronic rotator cuff tears [44,45]. In this study, miR-29a directly targeted COL3A1 3′-UTR together with decreased fibrosis marker expression, which underpinned the analysis of fibrosis-inhibitory action of miR-29a in subacromial bursa.…”

Lateral to medial fibro‐adipogenic degeneration are greater in infraspinatus than supraspinatus following nerve and tendon injury of murine rotator cuff

“…Intermediate‐stage of fibro‐adipogenesis at 2 weeks post‐TTDN, and 3. End‐stage fibro‐adipogenesis at 6 weeks post‐TTDN 13,14,20 . However, these analyses were based on capturing field‐of‐view images for small areas of tissue sections and therefore could not determine the anatomic direction and rate of injury progression.…”

“…Experimental RC tears in rats and mice involving the transection of supraspinatus and infraspinatus tendons (TT) along with the suprascapular nerve (DN) have replicated the marked degenerative fibrosis and fat accumulation found in these patients. [11][12][13] The rodent model of massive RC tears has been used by researchers to study the pathological progression of the disease and to improve their understanding of the cellular response [13][14][15] to injury, the molecular pathways that are responsible for it [16][17][18] and test therapeutic approaches to attenuate the progression of muscle degeneration. [19][20][21][22][23] One of the most commonly used assays for analysis of development of damage in injured RC is muscle histology.…”

Rotator Cuff Fibro‐Adipogenic Progenitors Demonstrate Highest Concentration, Proliferative Capacity, and Adipogenic Potential Across Muscle Groups

“…Furthermore, it is possible that differences in FAP quantity and differentiation profiles are due in part to variance in FAP subpopulations across muscles. Age‐related differences in FAP activation and microenvironments may also play a role in the types and degrees of muscle pathology that develop . Future work will focus on identifying any age differences, further characterizing FAPs, and investigating if there are any differences among subpopulations in their response to muscle injury that may play a role in pathology differences observed.…”