TY - UNPB

T1 - Phosphoproteomic identification of Xin as a novel requirement for skeletal muscle disuse atrophy

AU - Li, Zhencheng

AU - Jensen, Pia

AU - Abrigo, Johanna

AU - Henriquez-Olguin, Carlos

AU - Gingrich, Molly

AU - Rytter, Nicolai

AU - Gliemann, Lasse

AU - Richter, Erik A.

AU - Hawke, Thomas

AU - Cabello-Verrugio, Claudio

AU - Larsen, Martin R

AU - Jensen, Thomas Elbenhardt

N1 - bioRxiv preprint posted May 28, 2019.

PY - 2019/5/28

Y1 - 2019/5/28

N2 - Background: Immobilization of skeletal muscle in a stretched position is associated with marked protection against disuse atrophy. Some intramyocellular changes in known proteins and posttranslational modifications were previously linked to this phenomenon but there are likely many presently unknown proteins and post-translational modifications that contribute to this beneficial effect.Methods: To identify novel proteins and phosphorylation events involved in stretch-induced reduction of disuse atrophy, we conducted a global unbiased screen of the changes occurring in skeletal muscle in control vs. 1 day and 1 week stretched cast-immobilized mouse tibialis anterior muscle, using quantitative tandem mass spectrometry on HILIC-fractionated muscle peptides with follow-up studies in transgenic mice and humans.Results: Our mass spectrometry analyses detected 11714 phosphopeptides and 2081 proteins, of which 53 phosphopeptides and 5 proteins, 125 phosphopeptides and 43 proteins were deregulated after 1D and 7D of stretched immobilization, respectively. The sarcomere and muscle tendinous junction-associated putative multi-adaptor protein Xin was among the most highly upregulated proteins both in terms of phosphorylation and protein expression and was confirmed to increase with stretch but not disuse atrophy in mice and to increase and decrease with exercise and cast immobilization, respectively, in humans. Xin-/- mice were partially protected against disuse but not denervation atrophy in both stretched and flexed immobilized muscles compared to WT.Conclusion: This study identified Xin as a novel protein involved in disuse atrophy and also provides a resource to guide future hypothesis-driven investigations into uncovering critical factors in the protection against disuse atrophy.

AB - Background: Immobilization of skeletal muscle in a stretched position is associated with marked protection against disuse atrophy. Some intramyocellular changes in known proteins and posttranslational modifications were previously linked to this phenomenon but there are likely many presently unknown proteins and post-translational modifications that contribute to this beneficial effect.Methods: To identify novel proteins and phosphorylation events involved in stretch-induced reduction of disuse atrophy, we conducted a global unbiased screen of the changes occurring in skeletal muscle in control vs. 1 day and 1 week stretched cast-immobilized mouse tibialis anterior muscle, using quantitative tandem mass spectrometry on HILIC-fractionated muscle peptides with follow-up studies in transgenic mice and humans.Results: Our mass spectrometry analyses detected 11714 phosphopeptides and 2081 proteins, of which 53 phosphopeptides and 5 proteins, 125 phosphopeptides and 43 proteins were deregulated after 1D and 7D of stretched immobilization, respectively. The sarcomere and muscle tendinous junction-associated putative multi-adaptor protein Xin was among the most highly upregulated proteins both in terms of phosphorylation and protein expression and was confirmed to increase with stretch but not disuse atrophy in mice and to increase and decrease with exercise and cast immobilization, respectively, in humans. Xin-/- mice were partially protected against disuse but not denervation atrophy in both stretched and flexed immobilized muscles compared to WT.Conclusion: This study identified Xin as a novel protein involved in disuse atrophy and also provides a resource to guide future hypothesis-driven investigations into uncovering critical factors in the protection against disuse atrophy.

KW - Faculty of Science

KW - Skeletal muscle

KW - Disuse atrophy

KW - Human

KW - Xin

KW - Exercise

U2 - 10.1101/652479

DO - 10.1101/652479

M3 - Preprint

T3 - bioRxiv

BT - Phosphoproteomic identification of Xin as a novel requirement for skeletal muscle disuse atrophy

ER -