INTRODUCTION We evaluated the contribution of denervation-related molecular processes to rotator cuff muscle degeneration after tendon release. METHODS We assessed the levels of myogenic (myogenin and myogenic differentiation factor [myoD]) and pro-adipogenic (peroxisome proliferator-activated receptor gamma) transcription factors; the denervation-associated proteins tenascin-C, laminin-2, and calcium/calmodulin dependent kinase II (CaMKII); and cellular alterations in sheep after infraspinatus tenotomy (TEN), suprascapular neurectomy (NEU), or both (TEN-NEU). RESULTS Extracellular ground substance increased at the expense of contractile tissue 16 weeks after surgery, correlating with CaMKII isoform levels. Sheep undergoing NEU and TEN-NEU had exaggerated infraspinatus atrophy and increased fast fibers compared with TEN sheep. The βMCaMKII isoform levels increased with tenotomy, and myoD levels tripled after denervation and were associated with slow fibers. DISCUSSION In sheep, denervation did not affect muscle-to-fat conversion after tenotomy of the infraspinatus. Furthermore, concurrent neurectomy mitigated the loss of fast fibers after tenotomy by inducing a fast-contractile phenotype. This article is protected by copyright. All rights reserved.