"Get the Balance Right": Pathological Significance of Autophagy Perturbation in Neuromuscular Disorders

Abstract

Recent research has revealed that autophagy, a major catabolic process in cells, is dysregulated in several neuromuscular diseases and contributes to the muscle wasting caused by non-muscle disorders (e.g. cancer cachexia) or during aging (i.e. sarcopenia). From there, the idea arose to interfere with autophagy or manipulate its regulatory signalling to help restore muscle homeostasis and attenuate disease progression. The major difficulty for the development of therapeutic strategies is to restore a balanced autophagic flux, due to the dynamic nature of autophagy. Thus, it is essential to better understand the mechanisms and identify the signalling pathways at play in the control of autophagy in skeletal muscle. A comprehensive analysis of the autophagic flux and of the causes of its dysregulation is required to assess the pathogenic role of autophagy in diseased muscle. Furthermore, it is essential that experiments distinguish between primary dysregulation of autophagy (prior to disease onset) and impairments as a consequence of the pathology. Of note, in most muscle disorders, autophagy perturbation is not caused by genetic modification of an autophagy-related protein, but rather through indirect alteration of regulatory signalling or lysosomal function. In this review, we will present the mechanisms involved in autophagy, and those ensuring its tight regulation in skeletal muscle. We will then discuss as to how autophagy dysregulation contributes to the pathogenesis of neuromuscular disorders and possible ways to interfere with this process to limit disease progression.

Keywords: Autophagy; FoxO; MAP1LC3; dystrophy; mTORC1; mitophagy; myopathy; p62/SQSTM1; skeletal muscle; vacuole.

Fig.1

Overview of mechanisms and proteins involved in autophagy in mammals. In (macro)autophagy, initiation leads to the formation of a phagophore, which engulfs large cytoplasmic parts and expands to give rise to autophagosomes. Autophagy induction depends on the balance of several regulatory pathways converging on the Ulk1 complex (A). Autophagy ensures selective degradation of proteins and organelles, mediated by different autophagy cargo receptors (p62, Nbr1) and chaperone/co-chaperone proteins (Hsp, BAG3) (B). After fusion with the lysosomes and/or endosomes, degradation of the autolysosomal content by lysosomal enzymes permits recycling of metabolites. Of note, lysosomes are also involved in degradation associated with microautophagy and chaperone-mediated autophagy (CMA) (C). Red lines represent inhibition; green arrows show activation. Bcln1, Beclin1; MVB, multivesicular bodies; Ub, ubiquitin.

Fig.2

Neuromuscular disorders related to dysregulation of autophagy induction. In control (Ctrl) muscle, autophagy induction is determined by the state of the Ulk1 complex, which is inhibited by Akt/PKB-mTORC1 signalling and activated by the AMPK pathway. The autophagic flux varies depending on nutritive and stress stimuli, which can promote prolonged autophagy induction via FoxO-dependent expression of autophagy genes. In pathological conditions, excessive or insufficient autophagic flux may contribute to muscle damage. In DM1 and MDC1A, Akt/PKB inhibition would promote autophagy induction, while Akt/PKB-mTORC1 activation seems to restrict autophagic flux in XLMTM, COLVI-RM, DMD and laminopathies. Of note, autophagy induction may be enhanced in XLMTM due to abnormal Vps34 activation caused by Mtm1 deficiency. Treatments, which proved some efficacy in animal models, are indicated in green. Red lines represent inhibition; green arrows show activation. In pathological conditions, red and green arrows indicate abnormal inhibition and activation of signalling pathways, respectively. Black and white arrowheads in the hematein & eosin staining of muscle cross-sections indicate fat and degeneration regions, respectively; arrows show vacuolated fibres. The mutated proteins are indicated by an asterisk. COL, collagen; DG, dystroglycan; IR, insulin receptor; IRS, insulin receptor substrate; m, month; NOS, NO synthase; PI3K, phosphoinositide-3 kinase; ROS, reactive oxygen species; SF, splicing factor; SG, sarcoglycan; y, year. Scale bar, 100 μm.

Fig.3

Neuromuscular disorders related to defective autophagosome maturation or lysosomal dysfunction. In myopathies with rimmed vacuoles (RV) (e.g. IBMPFD and MFM), autophagic vesicles would enlarge due to blockade of the maturation and fusion steps, likely caused by the accumulation of protein aggregates. In IBMPFD, VCP deficiency may also directly alter autophagosome maturation. In lysosomal storage disorders (LSD), defective autophagosome maturation/fusion and/or altered degradation steps lead to the formation of autophagic vacuoles with sarcolemmal features (AVSF) or enlarged lysosomes; glycogen massively accumulates in these vesicles in GSDIIb and GSDII diseases. Centronuclear myopathies related to DNM2 (AD-CNM) deficiency may also involve a defect in maturation/fusion steps. Of note, lysosome biogenesis and autophagy induction seem to be perturbed in some of these diseases. Red lines represent inhibition; green arrows show activation. Arrows in the H&E-stained muscle cross-sections indicate vacuoles. The pathogenic protein is indicated by an asterisk. CryAB, α-crystallin B chain; Des, desmin; Flnc, filamin C; M6PR, mannose-6 phosphate receptor; Ub, ubiquitin; y, year. Scale bar, 100 μm.