“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.

Autophagy and mitophagy flux in young and aged skeletal muscle following chronic contractile activity

“…Furthermore, since mitophagy is highly dynamic, it is important to capture the turnover or ‘flux’ of this process, rather than relying on snapshot protein measurements of pathway components, or of the LC3‐II/LC3‐I ratio (Mizushima & Yoshimori, ; Castets et al . ; Klionsky, ; Yoshii & Mizushima, ). Thus, this study had two central aims: (1) to directly determine how autophagosome/mitophagy flux is changed in aged muscle, and (2) to determine how autophagosome/mitophagy flux adapts in response to a model of chronic exercise in both young and aged animals.…”

“…Nonetheless, little research has focused on the selective removal of organelles through mitophagy, a process also critical to maintaining organelle and muscle integrity. Furthermore, since mitophagy is highly dynamic, it is important to capture the turnover or 'flux' of this process, rather than relying on snapshot protein measurements of pathway components, or of the LC3-II/LC3-I ratio (Mizushima & Yoshimori, 2007;Castets et al 2016;Klionsky, 2016;Yoshii & Mizushima, 2017). Thus, this study had two central aims:…”

Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I

“…Autophagy as a major catabolic process essential for proteostasis has also been suggested to contribute to muscle alterations in DM1 (48). The involvement of autophagy in DM1 was largely deduced from the presence of autophagic vesicles and/or accumulation of autophagic markers in DM1 cells, but usually without dynamic measurement of the autophagic flux (13,14,17,19,36,37,49).…”

Differential diagnosis of vacuolar myopathies in the NGS era

“…Sixteen patients showed moderate (affecting <10%), 10 marked (10%–50%) and six severe (>50% of the muscle fibers in the sections examined) myopathic changes including myofibrillar disintegration, non‐subsarcolemmal nuclei, atrophy, basophilia and necrosis. By light microscopy, 16 biopsies exhibited numerous (>10) (rimmed) vacuoles, 10 biopsies had light (1–3) to moderate (3–10) vacuolar defects in the sections examined; in six patients a considerable vacuolar myopathy characterized by large abnormal autophagic vacuoles was evident on the ultrastructural level only (Table 3). In 18 cases, there was additional neurogenic muscle fiber atrophy.…”

“…Typical genetic causes include deficiencies in lysosomal enzymes. These defects disturb the lysosomal pathway which is a key element of the autophagy machinery (70), exemplified by glycogen storage disease II (GSD II; Pompe disease) caused by lysosomal alpha glucosidase deficiency, Danon disease caused by mutation of the lysosomal membrane receptor LAMP2 and X‐linked myopathy with excessive autophagy (XMEA) caused by mutation of the a V‐ATPase lysosomal proton channel (9,38).…”