Circulating Tetraspanins: From Markers to Mechanisms Driving Systemic Exercise Adaptation.

Exercise impr ov es cardiometa bolic health thr ough a range of systemic [ie , bey ond w orking skeletal muscle (SkM)] mec ha-nisms typically attributed to small molecules and peptide hormones. Recent discoveries have shown that the abundance and cargo of circulating small extracellular vesicles (sEVs) like exosomes ar e alter ed by exer cise , but linking these c hanges to SkM-deri v ed systemic exercise adaptations has been challenging. A key barrier to linking SkM sEVs to exercise adaptations is determining which of the hundreds of molecules that may be transported by SkM sEVs have functional relevance in the context of exer cise . One surprisingly untested str ate gy is to start with the most abundant sEV car go . Tetraspanins like CD81 are tr ansmembr ane protein hallmarks of sEVs. To date, CD81 has only been described as an sEV marker, not an instrument of sEV function. However, ∼ 30 yr of resear c h has established CD81 as a tr ansmembr ane adaptor protein that influences a variety of cellular functions by altering the organization of r ece ptor pr oteins within membranes. Multiple groups