Sarcostat mechanism: A promising therapeutic strategy for misfolded proteins in cardiomyopathy

Liu, Wei; Bu, Haisong

doi:10.1111/eci.13725

Cited by 1 publication

(2 citation statements)

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“…[13][14][15] This model was more recently referred to as the "sarcostat". 14,[16][17][18] Support for this model came from fluorescence recovery after photobleaching (FRAP) experiments with fluorescently tagged sarcomeric proteins, that show recovery of fluorescent-actin 19,20 , myotilin 21,22 , α-actinin 2 (ACTN2), telethonin, tropomyosin 1 (TPM1) 23 , and TTN 24 after bleaching within several hours. In the latter study it was even proposed that TTN molecules can move between adjacent sarcomeric complexes.…”

Section: Introductionmentioning

confidence: 99%

“…1112 According to the prevailing model of sarcomere maintenance, sarcomeres are maintained by cytoplasmic soluble protein pools with free recycling between pools and sarcomeres [13][14][15] . This model was more recently referred to as the "sarcostat" 14,[16][17][18] . Support for this model came from fluorescence recovery after photobleaching (FRAP) experiments with fluorescently tagged sarcomeric proteins, that show recovery of fluorescent-actin 19,20 , myotilin 21,22 , α-actinin 2 (ACTN2), telethonin, tropomyosin 1 (TPM1) 23 , and TTN 24 after bleaching within several hours.…”

Section: Introductionmentioning

confidence: 99%

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Imaging of existing and newly translated proteins elucidates mechanisms of sarcomere turnover

Douvdevany,

Erlich,

Haimovich-Caspi

et al. 2023

Preprint

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How the sarcomeric complex is continuously turned-over in long-living cardiomyocytes is unclear. Here, we imaged the exchange of old and new Halo-tagged sarcomeric proteins. We disprove the prevailing ‘protein pool’ model and instead show an ordered mechanism in which only newly translated proteins enter the sarcomeric complex while older ones are removed and degraded. We also show that degradation is independent of protein age, and that proteolytic extraction is a rate limiting step in the turnover. We imaged and quantified the turnover of expressed and endogenous sarcomeric proteins, including the giant protein titin, in cardiomyocytes in culture and in vivo, at the single cell and at the single sarcomere level. We show that replacement occurs at a similar rate within cells and across the heart and is markedly slower in adult cells. Our findings imply a new model of sarcomere turnover and sarcomeric subunit replacement.

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