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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

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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 1

Muscle-specific TP53INP2 gain of function reduces skeletal muscle mass in a transgenic mouse model (SKM-Tg).

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Muscle-specific TP53INP2 gain of function reduces skeletal muscle mass i...
(A) Tp53inp2 mRNA and protein levels in different mouse tissues. The skeletal muscle (SKM) used for mRNA analysis was tibialis anterior, and tissues from 3 different male mice were used. ***P < 0.001, skeletal muscle vs. the other tissues. (B) Confocal images showing TP53INP2 localization in transverse sections from the tibialis anterior muscle. Adult muscles were electrotransferred with TP53INP2-RFP. TP53INP2 is shown in red and nuclei are shown in blue (Hoechst33342 staining). Scale bar: 20 μm (left and middle columns); 5 μm (right column). Boxes in the middle column are shown at higher magnification to the right. (C) Quantification of TP53INP2 protein levels in tissue homogenates from WT and SKM-Tg mice (n = 4). Data are shown as relative TP53INP2 levels in WT mice within each tissue. Representative images from quadriceps homogenates are shown. (D) Weights of tibialis anterior, gastrocnemius, and quadriceps muscles from 4-month-old WT and SKM-Tg mice. (E) Body weight of WT and SKM-Tg mice. (F) Epididymal adipose tissue and liver weights from WT and SKM-Tg mice. (G) Food intake of WT and SKM-Tg mice. (H) Mean cross-sectional area (CSA) of 150 myofibers per each tibialis anterior muscle. Data in D to H were obtained from 6 WT and 6 SKM-Tg mice. (I) Representative images of hematoxylin/eosin staining from WT and SKM-Tg mice. Scale bar: 100 μm. Data represent mean ± SEM. *P < 0.05, ***P < 0.001 vs. control mice.
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