Autophagy-regulating TP53INP2 mediates muscle wasting and is repressed in diabetes
David Sala, … , Antonio L. Serrano, Antonio Zorzano
David Sala, … , Antonio L. Serrano, Antonio Zorzano
Published April 8, 2014
Citation Information: J Clin Invest. 2014;124(5):1914-1927. https://doi.org/10.1172/JCI72327.
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Research Article Endocrinology

Autophagy-regulating TP53INP2 mediates muscle wasting and is repressed in diabetes

Abstract

A precise balance between protein degradation and synthesis is essential to preserve skeletal muscle mass. Here, we found that TP53INP2, a homolog of the Drosophila melanogaster DOR protein that regulates autophagy in cellular models, has a direct impact on skeletal muscle mass in vivo. Using different transgenic mouse models, we demonstrated that muscle-specific overexpression of Tp53inp2 reduced muscle mass, while deletion of Tp53inp2 resulted in muscle hypertrophy. TP53INP2 activated basal autophagy in skeletal muscle and sustained p62-independent autophagic degradation of ubiquitinated proteins. Animals with muscle-specific overexpression of Tp53inp2 exhibited enhanced muscle wasting in streptozotocin-induced diabetes that was dependent on autophagy; however, TP53INP2 ablation mitigated experimental diabetes-associated muscle loss. The overexpression or absence of TP53INP2 did not affect muscle wasting in response to denervation, a condition in which autophagy is blocked, further indicating that TP53INP2 alters muscle mass by activating autophagy. Moreover, TP53INP2 expression was markedly repressed in muscle from patients with type 2 diabetes and in murine models of diabetes. Our results indicate that TP53INP2 negatively regulates skeletal muscle mass through activation of autophagy. Furthermore, we propose that TP53INP2 repression is part of an adaptive mechanism aimed at preserving muscle mass under conditions in which insulin action is deficient.

Authors

David Sala, Saška Ivanova, Natàlia Plana, Vicent Ribas, Jordi Duran, Daniel Bach, Saadet Turkseven, Martine Laville, Hubert Vidal, Monika Karczewska-Kupczewska, Irina Kowalska, Marek Straczkowski, Xavier Testar, Manuel Palacín, Marco Sandri, Antonio L. Serrano, Antonio Zorzano

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Figure 3

TP53INP2 increases basal autophagy in skeletal muscle by inducing the formation of autophagosomes.

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TP53INP2 increases basal autophagy in skeletal muscle by inducing the fo...
(A) Western blot analysis of LC3I and LC3II content in total homogenates of gastrocnemius muscles from WT and SKM-Tg mice or from control and SKM-KO mice. Representative images are shown. Mice were treated with chloroquine as indicated. (B) Overall proteolysis assessed as the rate of tyrosine released to the media in incubated extensor digitorum longus muscles (n = 14). (C) Autophagosomes were quantified by counting EGFP-LC3–positive dots normalized for cross-sectional area from tibialis anterior muscles transfected with EGFP-LC3 from WT and SKM-Tg mice fasted for 16 hours (n = 5). Representative images of transverse sections from adult tibialis anterior muscles transfected with EGFP-LC3 of WT and SKM-Tg mice are shown. Scale bar: 15 μm. (D) Confocal images of tibialis anterior muscle transverse sections showing colocalization between TP53INP2 and LC3. Adult muscles were transfected with TP53INP2-RFP and EGFP-LC3. TP53INP2 is stained in red, LC3 is stained in green, and nuclei are stained in blue (Hoechst33342 staining). Scale bar: 30 μm. Data represent mean ± SEM. *P < 0.05, **P < 0.01 vs. control values.