Skeletal muscle fibrosis and stiffness increase after rotator cuff tendon injury and neuromuscular compromise in a rat model

Abstract

Rotator cuff tears can cause irreversible changes (e.g., fibrosis) to the structure and function of the injured muscle(s). Fibrosis leads to increased muscle stiffness resulting in increased tension at the rotator cuff repair site. This tension influences repairability and healing potential in the clinical setting. However, the micro- and meso-scale structural and molecular sources of these whole-muscle mechanical changes are poorly understood. Here, single muscle fiber and fiber bundle passive mechanical testing was performed on rat supraspinatus and infraspinatus muscles with experimentally induced massive rotator cuff tears (Tenotomy) as well as massive tears with chemical denervation (Tenotomy+BTX) at 8 and 16 weeks post-injury. Titin molecular weight, collagen content, and myosin heavy chain profiles were measured and correlated with mechanical variables. Single fiber stiffness was not different between controls and experimental groups. However, fiber bundle stiffness was significantly increased at 8 weeks in the Tenotomy+BTX group compared to Tenotomy or control groups. Many of the changes were resolved by 16 weeks. Only fiber bundle passive mechanics was weakly correlated with collagen content. These data suggest that tendon injury with concomitant neuromuscular compromise results in extracellular matrix production and increases in stiffness of the muscle, potentially complicating subsequent attempts for surgical repair.

Chronic Degeneration Leads to Poor Healing of Repaired Massive Rotator Cuff Tears in Rats

“…5,15 Changes in rotator cuff muscle physiology, induced by tendon release and muscle retraction in the scapular fossa, can also lead to increased passive stiffness and increased repair site tension. 17,18,57 Additionally, retraction can potentially lead to suprascapular nerve impingement and palsy. 1,6,39,62 In previous work, it has been found that a single injection of botulinum toxin A after SS and IS tenotomy could lead to acute muscle changes such as increased muscle fiber bundle stiffness and collagen content at 8 weeks after injury, with such functional and biochemical changes associated with muscle paralysis being recovered by 16 weeks after injury.…”

“…32 Likewise, chronic detachment of both the SS and infraspinatus (IS) tendons can lead to substantial muscle and bone changes in a rodent model of rotator cuff disease, and these changes are magnified in the presence of short-term muscle paralysis. 56,57 A delay in repair after a single-tendon (ie, SS) injury of 3 weeks has been associated with a marked decrease in bone density, decreased material properties, and impaired organization. 12 A delay in rotator cuff repair after a single-tendon (ie, SS) injury led to increased repair site tension, which was strongly correlated with repair site stiffness, strength, and increased cross-sectional area.…”

“…18 While the rodent has been used as a model system for chronic tears, the severity of degeneration in muscle, tendon, and bone in the single-tendon injury model does not compare well with the degeneration observed in older patients with chronic tears. Therefore, atrophy and fibrosis have been accelerated in such models using botulinum toxin A 34,57 or suprascapular nerve injuries 36 to induce short-term paralysis or permanent muscle paralysis, respectively.…”

Investigating the cellular origin of rotator cuff muscle fatty infiltration and fibrosis after injury

“…It is postulated that increased fibrosis results in higher tension in the muscle in RC tears, thus making repair more challenging in chronic, retracted tears. In a clinical setting, fibrosis has been found in human RC tissue at time of repair and has been correlated with decreased force production and increased disruption of myofibril architecture 6,[22][23][24] . Fibrosis has also been identified as a direct cause of muscle dysfunction in muscular dystrophy.…”

Engineering Musculoskeletal Tissue Interfaces

“…The most common injuries which occur at the MTJ is seen in the rotator cuff, Achilles tendon, and hamstrings. Current approach for these injuries are suture repairs but these treatments have a high retear rate and high risk of fibrotic scar tissue formation at the wound site (Galatz et al, 2004;Vitale et al, 2007;Sato et al, 2014). In order to engineer MTJ-like constructs to regenerate these cases, a biomaterial platform should be developed which have characteristics of both tissues as well as the MTJ.…”