UC San Diego

One in five people have a rotator cuff tear, increasing with age to 50% of patients in the eighth decade of life. This creates a large burden on the healthcare system, as outcomes of tendon repair are poor and functional recovery even after successful tendon repair is limited. Strongly associated with rotator cuff tendon tears are irreversible muscle loss and muscle fatty infiltration, which serve as key clinical indicators of disease progression and predictors of surgical outcome. The prevailing biological and treatment paradigms have attributed these negative muscle changes to atrophy and subsequent space-filling by adipocytes. However, atrophy is a well-defined, self-limiting, and generally reversible response to unloading, which does not adequately explain the irreversibility of muscle loss in these patients. In human muscle biopsies, we discovered a novel phenotype of muscle fiber degeneration in which segments of muscle fiber membranes and cytoplasm are disrupted, leading to alternately hyper- and hypo-cellular degenerative regions. While muscle regeneration is increased in these biopsies, in some cases degenerative regions appear to resolve by adipocyte deposition within the fascicular architecture in a process of fatty replacement. Together with our finding that sarcomeres remodel normally in full-thickness but not massive tears, these data provide a compelling explanation for irreversibility of muscle loss in chronic, massive tears; total muscle volume is permanently reduced over time, and the remaining muscle is no longer sensitive to mechanical loading. After exhaustive characterization of small- and large-animal models of RCT in the context of these human findings, we determined that rabbit and sheep each adequately recapitulate the tissue-level degenerative processes found clinically. Using these models, we have begun to define the biological processes involved in chronic muscle degeneration, which include cellular stress and membrane damage responses, inhibition of growth and metabolism (particularly oxidative phosphorylation), prolonged inflammation, and competing processes of cell death and survival, while protein catabolic processes commonly associated with atrophy are notably absent. In conclusion, the findings of muscle degeneration and replacement of muscle fibers with adipose tissue described here provide a new paradigm for understanding and treating muscle loss in chronic rotator cuff disease.