Translational therapy from preclinical animal models for muscle degeneration after rotator cuff injury

Abstract

Chronic rotator cuff tears are debilitating diseases which significantly affect patients' quality of life and pose substantial financial burden to the society. The intraoperative reparability of injured tendon and postoperative probability of tendon retear are highly associated with the quality of torn muscles, specifically, the severity of muscle atrophy and fatty infiltration. Animal models that reproduce the characteristic muscle pathology after rotator cuff injury have been developed and used to provide insight into the underlying biology and pathophysiology. In this review, we briefly summarize the current information obtained from preclinical animal studies regarding the degenerative change of cuff muscle subsequent to tendon release and/or suprascapular nerve denervation. Importantly, we focus on the potential translational therapeutic targets or agents for the prevention or reversal of muscle atrophy and fatty infiltration. While further studies are warranted to assess the safety and efficacy of novel therapies derived from these preclinical animal research, we believe that their clinical translation for the treatment of rotator cuff disorders is on the horizon.

The translational potential of this article: Novel therapeutic strategies described in this review from preclinical animal studies hold a great translational potential for preventing or reversing rotator cuff muscle pathology, while further assessments on their safety and efficacy are warranted.

Keywords: Animal model; Fatty infiltration; Muscle atrophy; Rotator cuff tear; Suprascapular nerve denervation; Tenotomy.

Fig. 1

Schematic illustration showing injury to the suprascapular nerve following medial retraction of torn supraspinatus and infraspinatus tendons. Reprinted with permission from Ref. [50].

Fig. 2

The effect of calpain inhibition on muscle volume (A), muscle length (B) and muscle CSA (C) at 30 min, 2, 4, and 6 weeks postoperatively (CALP, n = 5; CALPSILD, n = 6). Time effects: ∗p ​< ​0.05, ∗∗p ​< ​0.01, ∗∗∗p ​< ​0.001 versus 30 ​min; ⁺p < 0.05, ⁺⁺p < 0.01, ⁺⁺⁺p < 0.001 versus 2 weeks; ^&p ​< ​0.05, ^&&&p ​< ​0.001 versus 4 weeks. Group effects: ^#p ​< ​0.05 versus CONTROL; ^$p ​< ​0.05, ^$$$p ​< ​0.001 versus operated shoulder at 30 ​min (D) The distribution of contractile, fatty and non-fatty connective tissue among groups prior to, and 2, 4, and 6 weeks after surgery (E) The slow-to-fast fiber shift was delayed with calpain inhibition for 2 weeks compared to the CONTROL group (CALP, n ​= ​5; CALPSILD, n ​= ​6). Time effects: ∗p ​< ​0.05, ∗∗p ​< ​0.01 versus PRE; ⁺p < 0.05, ⁺⁺p < 0.01 versus 2 weeks. Values are presented as means ​± ​SD. CALP: calpeptin-treated; CALPSILD: calpeptin and sildenafil-treated. Adapted and reprinted with permission from Ref. [27].

Fig. 3

(A) ​T ​+ ​D contributes to fatty infiltration within the supraspinatus muscle demonstrated by immunofluorescence staining for perilipin and DAPI. Scale bar ​= ​50 ​μm (B) The proportional areas of fat were significantly higher in the T ​+ ​D group. n ​= ​3 mice/group (C) The transcripts expression of adipocyte markers. n ​= ​5 mice/group (D) Increase of PDGFRα⁺ MSCs in the T+D group shown by Western blotting, immunofluorescent images and semi-quantitative counting of PDGFRα⁺ cells per microscopic field (214 μ m ​× ​214 μ m). Scale bar ​= ​30 ​μm, n ​= ​3 mice/group (E) The effect of imatinib on the suppression of fatty infiltration illustrated by immunofluorescence staining for perilipin with DAPI (scale bar ​= ​100 ​μm) or laminin and PDGFRα with DAPI (scale bar ​= ​30 ​μm) (n ​= ​3 mice/group), as well as Western blotting (2 mice/group) (F) The transcripts expression of adipocyte markers after imatinib treatment. n ​= ​5 mice/group. Values are presented as means ​± ​SD. TT, tendon transection; DN, suprascapular nerve denervation; T ​+ ​D, tendon transection and denervation. ∗p ​< ​0.05; ∗∗p ​< ​0.01; ∗∗∗p ​< ​0.001; ∗∗∗∗p ​< ​0.0001. Adapted and reprinted with permission from Ref. [83].