Meyer GA, Gibbons MC, Sato E, Lane JG, Ward SR, Engler AJ.
Chronic rotator cuff (RC) tears are a common and debilitating injury,
characterized by dramatic expansion of adipose tissue, muscle atrophy, and
limited functional recovery. The role of adipose expansion in RC pathology is
unknown; however, given the identified paracrine/endocrine regulation by other
adipose depots, it likely affects tissue function outside its boundaries.
Therefore, we characterized the epimuscular (EM) fat depot of the human rotator
cuff, defined its response to RC tears, and evaluated its influence on myogenesis
in vitro. EM fat biopsies exhibited morphological and functional features of
human beige fat compared with patient-matched s.c. biopsies, which appeared
whiter. The transcriptional profile of EM fat and isolated EM adipose-derived
stem cells (ASCs) shifted as a function of the tear state; EM fat from intact
cuffs had significantly elevated expression of the genes associated with
uncoupled respiration, and the EM fat from torn cuffs had increased expression of
beige-selective genes. EM ASC cocultures with human- and mouse-derived myogenic
cells exhibited increased levels of myogenesis compared with s.c. cultures.
Increased fusion and decreased proliferation of myogenic cells, rather than
changes to the ASCs, were found to underlie this effect. Taken together, these
data suggest that EM fat in the human rotator cuff is a novel beige adipose depot
influenced by cuff state with therapeutic potential for promoting myogenesis in
Rotator cuff tears affect millions of
people in the U.S.; however, current interventions are hindered by persistent
muscle degeneration. This study identifies the therapeutic potential for muscle
recovery in the epimuscular fat in the rotator cuff, previously considered a
negative feature of the pathology, and finds that this fat is beige, rather than
white. This is important for two reasons. First, the stem cells that were
isolated from this beige fat are more myogenic than those from white fat, which
have been the focus of stem cell-based therapies to date, suggesting epimuscular
fat could be a better stem cell source to augment rotator cuff repair. Second,
these beige stem cells promote myogenesis in neighboring cells in culture,
suggesting the potential for this fat to be manipulated therapeutically to
promote muscle recovery through secreted signals.
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