Skeletal Muscle Homeostasis in Duchenne Muscular Dystrophy: Modulating Autophagy as a Promising Therapeutic Strategy

Abstract

Muscular dystrophies are a group of genetic and heterogeneous neuromuscular disorders characterized by the primary wasting of skeletal muscle. In Duchenne muscular dystrophy (DMD), the most severe form of these diseases, the mutations in the dystrophin gene lead to muscle weakness and wasting, exhaustion of muscular regenerative capacity, and chronic local inflammation leading to substitution of myofibers by connective and adipose tissue. DMD patients suffer from continuous and progressive skeletal muscle damage followed by complete paralysis and death, usually by respiratory and/or cardiac failure. No cure is yet available, but several therapeutic approaches aiming at reversing the ongoing degeneration have been investigated in preclinical and clinical settings. Autophagy is an important proteolytic system of the cell and has a crucial role in the removal of proteins, aggregates, and organelles. Autophagy is constantly active in skeletal muscle and its role in tissue homeostasis is complex: at high levels, it can be detrimental and contribute to muscle wasting; at low levels, it can cause weakness and muscle degeneration, due to the unchecked accumulation of damaged proteins and organelles. The causal relationship between DMD pathogenesis and dysfunctional autophagy has been recently investigated. At molecular level, the Akt axis is one of the key dysregulated pathways, although the molecular events are not completely understood. The aim of this review is to describe and discuss the clinical relevance of the recent advances dissecting autophagy and its signaling pathway in DMD. The picture might pave the way for the development of interventions that are able to boost muscle growth and/or prevent muscle wasting.

Loss of lipin 1‐mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice

“…This is a critical step in recruiting mitochondria destined for autophagy to nascent autophagosomes. Abnormalities in lysosomal function and autophagy have been linked to several forms of muscle injury and myopathy, including muscular dystrophy (46)(47)(48)(49). How deficits in mitophagy or macroautophagy in general lead to muscle injury and rhabdomyolysis remains to be determined.…”

Effects of non‐euphoric plant cannabinoids on muscle quality and performance of dystrophic mdx mice

“…In addition to the lack of dystrophin, the progressive decline in the autophagy process has been recently highlighted as one of the main causes of the inefficient function of satellite cells during DMD progression (Fiacco et al, ). These results, in agreement with previous findings, suggested that autophagy represents a promising target for the treatment of DMD (Sandri et al, ; De Palma et al, ; Fiacco et al, ).…”

Perturbation of PTEN-PI3K/AKT Signalling Impaired Autophagy Modulation in Dystrophin-Deficient Myoblasts

“…Many studies have been carried out concerning PI3K/Akt impairment in the mdx mouse as well as in DMD in humans. Activation of Akt has been found to be higher in the mdx mouse (6,9) and also in DMD patients (10). As Akt plays a major role in cell signalling, its impairment leads to various defects in downstream protein signalling, including cell proliferation, differentiation, apoptosis, autophagy and protein synthesis perturbation.…”

“…Autophagy is defective in mdx mice (16) and DMD humans (17). Restoration of beclin1 levels in Col6a1 -/animals and long-term exposure to a low-protein diet (9,13) can reactivate autophagy and partly ameliorate the dystrophic features/phenotype. Col6a1 -/animals display an impairment of basal autophagy, which determines the persistence of dysfunctional organelles in muscle fibres leading to muscle degeneration (13).…”