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Skeletal muscle homeostasis in duchenne muscular dystrophy: modulating autophagy as a promising therapeutic strategy.

De Palma C, Perrotta C, Pellegrino P, Clementi E, Cervia D - Front Aging Neurosci (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences "L. Sacco", National Research Council-Institute of Neuroscience, University Hospital "L. Sacco", University of Milan , Milan , Italy.

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.

No MeSH data available.


Related in: MedlinePlus

Schematic illustration of the correlation between autophagy and Duchenne muscular dystrophy. Basal autophagy levels are required for muscle homeostasis and for the maintenance of healthy myofibers. In DMD, muscle autophagy is impaired contributing to muscle degeneration. This autophagy inhibition is dependent on the iper-activation of Akt–mTOR axis. Treatments with rapamycin or low-protein diet, acting on Akt pathway, restore autophagy ameliorating DMD muscle phenotype and function. The impaired autophagy may also occur independently of Akt. Treatments with AMPK agonists, which increase AMPK activation, counteract the Akt-independent axes enhancing autophagy and inducing a positive effect in DMD muscle.
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Figure 1: Schematic illustration of the correlation between autophagy and Duchenne muscular dystrophy. Basal autophagy levels are required for muscle homeostasis and for the maintenance of healthy myofibers. In DMD, muscle autophagy is impaired contributing to muscle degeneration. This autophagy inhibition is dependent on the iper-activation of Akt–mTOR axis. Treatments with rapamycin or low-protein diet, acting on Akt pathway, restore autophagy ameliorating DMD muscle phenotype and function. The impaired autophagy may also occur independently of Akt. Treatments with AMPK agonists, which increase AMPK activation, counteract the Akt-independent axes enhancing autophagy and inducing a positive effect in DMD muscle.

Mentions: The defect in autophagy of mdx mouse muscles is accompanied by persistent activation of the Akt–mTOR axis (Figure 1) and its related autophagy-inhibiting pathways, and the concomitant downregulation of several autophagy-inducing genes (Dogra et al., 2006; Peter and Crosbie, 2006; De Palma et al., 2012). In particular, Akt activation has been established to occur at very early, pre-necrotic stages of disease pathogenesis, with a progressive increase with disease worsening (Peter and Crosbie, 2006). This high activation of Akt stimulates in turn the mTOR-dependent pathways whereas the mTOR-independent axis is not significantly altered (Dogra et al., 2006; Peter and Crosbie, 2006). The involvement of the mTOR axis in the pathogenesis of mdx mice is demonstrated also by the effects of the mTOR-targeting, immunosuppressant drug rapamycin. Oral or injected rapamycin treatment has been shown to improve histopathological features of dystrophy (Eghtesad et al., 2011) and the treatment with rapamycin-loaded nanoparticles (RNPs) has been shown to increase skeletal muscle strength in both young and adult mice concomitantly to an increased mTOR-dependent autophagy (Bibee et al., 2014). Consistently, mdx mice treatment with a long-term low-protein diet reactivates autophagy in muscle fibers, with increased lipidation of LC3, reduced levels of p62, normalization of Akt and mTOR signaling, a reduced accumulation of damaged organelles, and a significant recovery of muscle inflammation, fibrosis, myofiber damage and muscle function (De Palma et al., 2012). Since the long-term low-protein diet was shown to preserve the regenerating ability of mdx mouse muscle, it is tempting to speculate that physiological levels of autophagy maintain the number and function of myogenic precursor cells.


Skeletal muscle homeostasis in duchenne muscular dystrophy: modulating autophagy as a promising therapeutic strategy.

De Palma C, Perrotta C, Pellegrino P, Clementi E, Cervia D - Front Aging Neurosci (2014)

Schematic illustration of the correlation between autophagy and Duchenne muscular dystrophy. Basal autophagy levels are required for muscle homeostasis and for the maintenance of healthy myofibers. In DMD, muscle autophagy is impaired contributing to muscle degeneration. This autophagy inhibition is dependent on the iper-activation of Akt–mTOR axis. Treatments with rapamycin or low-protein diet, acting on Akt pathway, restore autophagy ameliorating DMD muscle phenotype and function. The impaired autophagy may also occur independently of Akt. Treatments with AMPK agonists, which increase AMPK activation, counteract the Akt-independent axes enhancing autophagy and inducing a positive effect in DMD muscle.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4109521&req=5

Figure 1: Schematic illustration of the correlation between autophagy and Duchenne muscular dystrophy. Basal autophagy levels are required for muscle homeostasis and for the maintenance of healthy myofibers. In DMD, muscle autophagy is impaired contributing to muscle degeneration. This autophagy inhibition is dependent on the iper-activation of Akt–mTOR axis. Treatments with rapamycin or low-protein diet, acting on Akt pathway, restore autophagy ameliorating DMD muscle phenotype and function. The impaired autophagy may also occur independently of Akt. Treatments with AMPK agonists, which increase AMPK activation, counteract the Akt-independent axes enhancing autophagy and inducing a positive effect in DMD muscle.
Mentions: The defect in autophagy of mdx mouse muscles is accompanied by persistent activation of the Akt–mTOR axis (Figure 1) and its related autophagy-inhibiting pathways, and the concomitant downregulation of several autophagy-inducing genes (Dogra et al., 2006; Peter and Crosbie, 2006; De Palma et al., 2012). In particular, Akt activation has been established to occur at very early, pre-necrotic stages of disease pathogenesis, with a progressive increase with disease worsening (Peter and Crosbie, 2006). This high activation of Akt stimulates in turn the mTOR-dependent pathways whereas the mTOR-independent axis is not significantly altered (Dogra et al., 2006; Peter and Crosbie, 2006). The involvement of the mTOR axis in the pathogenesis of mdx mice is demonstrated also by the effects of the mTOR-targeting, immunosuppressant drug rapamycin. Oral or injected rapamycin treatment has been shown to improve histopathological features of dystrophy (Eghtesad et al., 2011) and the treatment with rapamycin-loaded nanoparticles (RNPs) has been shown to increase skeletal muscle strength in both young and adult mice concomitantly to an increased mTOR-dependent autophagy (Bibee et al., 2014). Consistently, mdx mice treatment with a long-term low-protein diet reactivates autophagy in muscle fibers, with increased lipidation of LC3, reduced levels of p62, normalization of Akt and mTOR signaling, a reduced accumulation of damaged organelles, and a significant recovery of muscle inflammation, fibrosis, myofiber damage and muscle function (De Palma et al., 2012). Since the long-term low-protein diet was shown to preserve the regenerating ability of mdx mouse muscle, it is tempting to speculate that physiological levels of autophagy maintain the number and function of myogenic precursor cells.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences "L. Sacco", National Research Council-Institute of Neuroscience, University Hospital "L. Sacco", University of Milan , Milan , Italy.

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.

No MeSH data available.


Related in: MedlinePlus