Inhibition of calpain delays early muscle atrophy after rotator cuff tendon release in sheep

• Published in: Physiological reports 2018-11, Vol.6 (21), p.e13833-n/a
• Main Authors: Ruoss, Severin, Kindt, Philipp, Oberholzer, Linus, Rohner, Marco, Jungck, Ladina, Abdel‐Aziz, Sara, Fitze, Daniel, Rosskopf, Andrea B., Klein, Karina, Rechenberg, Brigitte, Gerber, Christian, Wieser, Karl, Flück, Martin
• Format: Article
• Language: English
• Subjects: Adaptation; Atrophy; Calpain; Cellular Physiology; costamere; Injuries; Muscle Physiology; Original Research; Physiology; Preservation; Rotator cuff; rotator cuff tear; Sarcolemma; Sildenafil; Talin; tenotomy; Unloading
• ISSN: 2051-817X
• DOI: 10.14814/phy2.13833

Chronic rotator cuff (RC) tears are characterized by retraction, fat accumulation, and atrophy of the affected muscle. These features pose an intractable problem for surgical repair and subsequent recovery, and their prevention may be easier than reversal. Using an established ovine model, we tested the hypothesis that inhibition of the protease calpain mitigates m. infraspinatus atrophy by preservation of the myofibers’ structural anchors in the sarcolemma (the costameres). Already 2 weeks of distal tendon release led to a reduction in muscle volume (−11.6 ± 9.1 cm3, P = 0.038) and a 8.3% slow‐to‐fast shift of the fiber area (P = 0.046), which were both entirely abolished by chronic local administration of the calpain inhibitor calpeptin alone, and in combination with sildenafil. Calpain inhibition blunted the retraction of the muscle‐tendon unit by 0.8–1.0 cm (P = 0.020) compared with the control group, and prevented cleavage of the costameric protein talin. Calpain 1 and 2 protein levels increased in the medicated groups after 4 weeks, counteracting the efficacy of calpeptin. Hence atrophic changes emerged after 4 weeks despite ongoing treatment. These findings suggest that the early muscular adaptations in the specific case of RC tear in the ovine model are indistinguishable from the atrophy and slow‐to‐fast fiber transformation observed with conventional unloading and can be prevented for 2 weeks. Concluding, calpain is a potential target to extend the temporal window for reconstruction of the ruptured RC tendon before recovery turns impossible. This study investigated on the muscular, molecular, and cellular levels whether calpain inhibition mitigates muscle atrophy and retraction after rotator cuff tear in the ovine model. We found atrophy and the shift from slow to fast fibers were prevented for the first 2 weeks after surgical tendon release. Retraction and cleavage of the costamere‐associated structural protein talin were mitigated for up to 6 weeks. These results provide novel insight into the early muscle adaptation to tendon release and propose a new medication that may slow down the rotator cuff disease process.