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 2

TP53INP2-specific ablation in skeletal muscle causes muscle hypertrophy in a knockout mouse model (SKM-KO).

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TP53INP2-specific ablation in skeletal muscle causes muscle hypertrophy ...
(A) Genomic structure of Tp53inp2 gene showing 5 exons and the corresponding 4 introns. LoxP sequences were inserted into introns 2 and 4. After Cre recombinase action, exons 3 and 4 were excised, eliminating the initiation codon. (B) Quantification of TP53INP2 protein levels in tissue homogenates from control (C) (nonexpressing Cre Tp53inp2loxP/loxP mice) and SKM-KO mice (expressing Cre Tp53inp2loxP/loxP mice). Representative images from quadriceps homogenates are shown. Data are shown as relative TP53INP2 levels in control mice within each tissue. (C) Weights of tibialis anterior, gastrocnemius, and quadriceps muscles from 4-month-old control and SKM-KO mice. (D) Body weight of control and SKM-KO mice. (E) Epididymal adipose tissue and liver weights from control and SKM-KO mice. (F) Food intake of control and SKM-KO mice. (G) Mean cross-sectional area of 150 myofibers per each tibialis anterior muscle. (H) Lean tissue volume of the right hind limb of 4-month-old control and SKM-KO mice. Data in C to H were obtained from 6 control and 10 SKM-KO mice. (I) Representative images of hematoxylin/eosin staining from control and SKM-KO mice Scale bar: 100 μm. Data represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control mice.