Polycystin-2 Is Required for Starvation- and Rapamycin-Induced Atrophy in Myotubes.

Catalina Kretschmar,Cecilia Hernando,Mauricio Budini,Daniel Peña-Oyarzun,María Paz Hernández-Cáceres,Rodrigo Troncoso,Alfredo Criollo,Nadia Hernández-Moya,Sergio Lavandero,Valentina Parra,Eugenia Morselli,Alfredo Molina-Berríos

doi:10.3389/fendo.2019.00280

Abstract

Muscle atrophy involves a massive catabolism of intracellular components leading to a significant reduction in cellular and tissue volume. In this regard, autophagy, an intracellular mechanism that degrades proteins and organelles, has been implicated with muscle breakdown. Recently, it has shown that polycystin-2 (PC2), a membrane protein that belongs to the transient receptor potential (TRP) family, is required for the maintenance of cellular proteostasis, by regulating autophagy in several cell types. The role of PC2 in the control of atrophy and autophagy in skeletal muscle remains unknown. Here, we show that PC2 is required for the induction of atrophy in C2C12 myotubes caused by nutrient deprivation or rapamycin exposure. Consistently, overexpression of PC2 induces atrophy in C2C12 myotubes as indicated by decreasing of the myogenic proteins myogenin and caveolin-3. In addition, we show that inhibition of mTORC1, by starvation or rapamycin is inhibited in cells when PC2 is silenced. Importantly, even if PC2 regulates mTORC1, our results show that the regulation of atrophy by PC2 is independent of autophagy. This study provides novel evidence regarding the role of PC2 in skeletal muscle cell atrophy.

Highlights

Atrophy defined as a decrease in the mass and size of tissues or cells, is caused by a massive loss of proteins, cytoplasm, and organelles
The level of p62/SQSTM1 decreases when cells are exposed to Earle’s Balanced Salt Solution (EBSS) or treated with rapamycin (Figures 1A,E,F,J), confirming that autophagy is upregulated in C2C12 myotubes following the aforementioned treatments
Given that PC2 regulates autophagy, and that autophagy is enhanced by action of different atrophy inducers in skeletal muscle cells, we evaluated if PC2 is required for atrophy in C2C12 myotubes exposed to nutrient deprivation or rapamycin

Summary

Introduction

Atrophy defined as a decrease in the mass and size of tissues or cells, is caused by a massive loss of proteins, cytoplasm, and organelles. Other studies have shown that the mechanistic target of rapamycin complex 1, mTOR, a constitutive kinase protein that inhibits autophagy, blocks atrophy in muscle and other cell types [11]. In this regard, muscle-specific mTOR knockout mice present a severe muscle atrophy phenotype. Inhibition of mTOR, induced by nutrient restriction or treatment with rapamycin (which inhibits mTORC1), causes autophagy and atrophy in skeletal muscle [11, 12, 14, 15]. In renal epithelial cells and human embryonic stem cell-derived cardiomyocytes, PC2 is required for fluid flow- and glucose starvation-induced autophagy, respectively [18, 19]

Methods

Results

Conclusion