Idiopathic inflammatory myopathy human derived cells retain their ability to increase mitochondrial function

Carla Basualto-Alarcón,Félix A Urra,Jorge A Bevilacqua,María Francisca Bozán,J César Cárdenas,Alejandra Trangulao,Fabián Jaña,Jianhua Zhang

doi:10.1371/journal.pone.0242443

Abstract

Idiopathic Inflammatory Myopathies (IIMs) have been studied within the framework of autoimmune diseases where skeletal muscle appears to have a passive role in the illness. However, persiting weakness even after resolving inflammation raises questions about the role that skeletal muscle plays by itself in these diseases. "Non-immune mediated" hypotheses have arisen to consider inner skeletal muscle cell processes as trigger factors in the clinical manifestations of IIMs. Alterations in oxidative phosphorylation, ATP production, calcium handling, autophagy, endoplasmic reticulum stress, among others, have been proposed as alternative cellular pathophysiological mechanisms. In this study, we used skeletal muscle-derived cells, from healthy controls and IIM patients to determine mitochondrial function and mitochondrial ability to adapt to a metabolic stress when deprived of glucose. We hypothesized that mitochondria would be dysfunctional in IIM samples, which was partially true in normal glucose rich growing medium as determined by oxygen consumption rate. However, in the glucose-free and galactose supplemented condition, a medium that forced mitochondria to function, IIM cells increased their respiration, reaching values matching normal derived cells. Unexpectedly, cell death significantly increased in IIM cells under this condition. Our findings show that mitochondria in IIM is functional and the decrease respiration observed is part of an adaptative response to improve survival. The increased metabolic function obtained after forcing IIM cells to rely on mitochondrial synthesized ATP is detrimental to the cell's viability. Thus, therapeutic interventions that activate mitochondria, could be detrimental in IIM cell physiology, and must be avoided in patients with IIM.

Highlights

Idiopathic Inflammatory Myopathies (IIMs) are the most frequent acquired myopathies observed in clinical practice [1] and represent a heterogeneous group of chronic, subacute, or acute acquired muscle disorders of unknown etiology
Myotubes and myoblasts are traditionally cultured in high glucose growing media, and our first attempts to bioenergetically characterize control and IIMderived cells were conducted in this scenario
Real time oxygen consumption measurements, as indicators of mitochondrial respiration, revealed that in IIM-derived cells, mitochondria exhibit a significantly lower basal oxygen consumption rate (OCR) compared to normal cells (Fig 1A and 1B)

Summary

Introduction

Idiopathic Inflammatory Myopathies (IIMs) are the most frequent acquired myopathies observed in clinical practice [1] and represent a heterogeneous group of chronic, subacute, or acute acquired muscle disorders of unknown etiology. They share the common feature of muscle inflammation which leads to generalized weakness. A growing body of evidence supports the view that other mechanisms might be involved in the pathogenesis of IIM This evidence has led some to argue that the cause of muscle dysfunction is far more complex than just immune- mediated inflammation [2]. The marked muscle atrophy and impaired muscle function seen in DM and PM patients, even after treatment, have been associated with a hypothetical metabolic dysfunction [14]

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