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Enhanced autophagy as a potential mechanism for the improved physiological function by simvastatin in muscular dystrophy.

Whitehead NP - Autophagy (2016)

Bottom Line: Statins decrease CYBB/NOX2 expression and activity and stimulate autophagy in skeletal muscle.This was accompanied by reduced muscle damage, inflammation and fibrosis, and increased muscle force production.Our data suggest that increased autophagy may be a potential mechanism by which simvastatin improves skeletal muscle health and function in muscular dystrophy.

View Article: PubMed Central - PubMed

Affiliation: a Department of Physiology and Biophysics , University of Washington , Seattle , WA.

ABSTRACT
Autophagy has recently emerged as an important cellular process for the maintenance of skeletal muscle health and function. Excessive autophagy can trigger muscle catabolism, leading to atrophy. In contrast, reduced autophagic flux is a characteristic of several muscle diseases, including Duchenne muscular dystrophy, the most common and severe inherited muscle disorder. Recent evidence demonstrates that enhanced reactive oxygen species (ROS) production by CYBB/NOX2 impairs autophagy in muscles from the dmd/mdx mouse, a genetic model of Duchenne muscular dystrophy. Statins decrease CYBB/NOX2 expression and activity and stimulate autophagy in skeletal muscle. Therefore, we treated dmd/mdx mice with simvastatin and showed decreased CYBB/NOX2-mediated oxidative stress and enhanced autophagy induction. This was accompanied by reduced muscle damage, inflammation and fibrosis, and increased muscle force production. Our data suggest that increased autophagy may be a potential mechanism by which simvastatin improves skeletal muscle health and function in muscular dystrophy.

No MeSH data available.


Related in: MedlinePlus

Simvastatin inhibits oxidative stress by CYBB/NOX2, which enhances autophagy and improves muscle health and function in muscular dystrophy. The loss of DMD/dystrophin results in the upregulation of CYBB/NOX2. ROS produced by CYBB/NOX2 causes oxidative stress. This leads to muscle damage, inflammation, and fibrosis, which culminate in the impairment of contractile function. ROS also activate SRC kinase, which inhibits autophagy via the AKT-MTOR pathway. RAC1 stimulates CYBB/NOX2 activity and also activates MTOR, both leading to autophagy dysfunction. Simvastatin enhances autophagy by reducing the expression of CYBB/NOX2 as well as preventing the membrane targeting of RAC1, by blocking isoprenylation. Through inhibition of these deleterious pathways, which lead to muscle damage, inflammation and fibrosis, simvastatin provides substantial improvement in the function of dystrophic muscles.
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f0001: Simvastatin inhibits oxidative stress by CYBB/NOX2, which enhances autophagy and improves muscle health and function in muscular dystrophy. The loss of DMD/dystrophin results in the upregulation of CYBB/NOX2. ROS produced by CYBB/NOX2 causes oxidative stress. This leads to muscle damage, inflammation, and fibrosis, which culminate in the impairment of contractile function. ROS also activate SRC kinase, which inhibits autophagy via the AKT-MTOR pathway. RAC1 stimulates CYBB/NOX2 activity and also activates MTOR, both leading to autophagy dysfunction. Simvastatin enhances autophagy by reducing the expression of CYBB/NOX2 as well as preventing the membrane targeting of RAC1, by blocking isoprenylation. Through inhibition of these deleterious pathways, which lead to muscle damage, inflammation and fibrosis, simvastatin provides substantial improvement in the function of dystrophic muscles.

Mentions: Several skeletal muscle diseases are characterized by dysregulation of autophagy. Excessive autophagy is associated with muscle atrophy while reduced autophagic flux is evident in several inherited muscle diseases. Recently, a number of studies have shown that the autophagy process is impaired in muscles from both dmd/mdx mice and Duchenne muscular dystrophy patients, as shown by reduced expression of the autophagy marker MAP1LC3B/LC3B (microtubule associated protein 1 light chain 3 beta) and increased accumulation of the protein SQSTM1/p62, indicative of damaged protein aggregate accumulation due to impaired autophagic flux. Recent evidence showed that CYBB/NOX2 (cytochrome b-245, beta polypeptide) plays a key role in the inhibition of autophagy in dmd/mdx mouse muscle. We and others have demonstrated that increased production of reactive oxygen species (ROS) by CYBB/NOX2 mediates many deleterious pathways in dystrophic muscles. CYBB/NOX2 is upregulated and its activity is very sensitive to mechanical stretch in muscles of dmd/mdx mice compared to normal, WT mice. The increased ROS production by CYBB/NOX2 triggers Ca2+ entry through stretch-activated ion channels. Together, the ROS and Ca2+ increase membrane permeability via lipid peroxidation, and induce muscle damage and reduced force production. CYBB/NOX2-derived ROS also activates SRC kinase, which, in turn, stimulates the AKT-MTOR pathway, leading to autophagy inhibition (Fig. 1). Therefore, drugs that inhibit CYBB/NOX2 should enhance autophagy and improve health and function in dystrophic muscles.Figure 1.


Enhanced autophagy as a potential mechanism for the improved physiological function by simvastatin in muscular dystrophy.

Whitehead NP - Autophagy (2016)

Simvastatin inhibits oxidative stress by CYBB/NOX2, which enhances autophagy and improves muscle health and function in muscular dystrophy. The loss of DMD/dystrophin results in the upregulation of CYBB/NOX2. ROS produced by CYBB/NOX2 causes oxidative stress. This leads to muscle damage, inflammation, and fibrosis, which culminate in the impairment of contractile function. ROS also activate SRC kinase, which inhibits autophagy via the AKT-MTOR pathway. RAC1 stimulates CYBB/NOX2 activity and also activates MTOR, both leading to autophagy dysfunction. Simvastatin enhances autophagy by reducing the expression of CYBB/NOX2 as well as preventing the membrane targeting of RAC1, by blocking isoprenylation. Through inhibition of these deleterious pathways, which lead to muscle damage, inflammation and fibrosis, simvastatin provides substantial improvement in the function of dystrophic muscles.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835971&req=5

f0001: Simvastatin inhibits oxidative stress by CYBB/NOX2, which enhances autophagy and improves muscle health and function in muscular dystrophy. The loss of DMD/dystrophin results in the upregulation of CYBB/NOX2. ROS produced by CYBB/NOX2 causes oxidative stress. This leads to muscle damage, inflammation, and fibrosis, which culminate in the impairment of contractile function. ROS also activate SRC kinase, which inhibits autophagy via the AKT-MTOR pathway. RAC1 stimulates CYBB/NOX2 activity and also activates MTOR, both leading to autophagy dysfunction. Simvastatin enhances autophagy by reducing the expression of CYBB/NOX2 as well as preventing the membrane targeting of RAC1, by blocking isoprenylation. Through inhibition of these deleterious pathways, which lead to muscle damage, inflammation and fibrosis, simvastatin provides substantial improvement in the function of dystrophic muscles.
Mentions: Several skeletal muscle diseases are characterized by dysregulation of autophagy. Excessive autophagy is associated with muscle atrophy while reduced autophagic flux is evident in several inherited muscle diseases. Recently, a number of studies have shown that the autophagy process is impaired in muscles from both dmd/mdx mice and Duchenne muscular dystrophy patients, as shown by reduced expression of the autophagy marker MAP1LC3B/LC3B (microtubule associated protein 1 light chain 3 beta) and increased accumulation of the protein SQSTM1/p62, indicative of damaged protein aggregate accumulation due to impaired autophagic flux. Recent evidence showed that CYBB/NOX2 (cytochrome b-245, beta polypeptide) plays a key role in the inhibition of autophagy in dmd/mdx mouse muscle. We and others have demonstrated that increased production of reactive oxygen species (ROS) by CYBB/NOX2 mediates many deleterious pathways in dystrophic muscles. CYBB/NOX2 is upregulated and its activity is very sensitive to mechanical stretch in muscles of dmd/mdx mice compared to normal, WT mice. The increased ROS production by CYBB/NOX2 triggers Ca2+ entry through stretch-activated ion channels. Together, the ROS and Ca2+ increase membrane permeability via lipid peroxidation, and induce muscle damage and reduced force production. CYBB/NOX2-derived ROS also activates SRC kinase, which, in turn, stimulates the AKT-MTOR pathway, leading to autophagy inhibition (Fig. 1). Therefore, drugs that inhibit CYBB/NOX2 should enhance autophagy and improve health and function in dystrophic muscles.Figure 1.

Bottom Line: Statins decrease CYBB/NOX2 expression and activity and stimulate autophagy in skeletal muscle.This was accompanied by reduced muscle damage, inflammation and fibrosis, and increased muscle force production.Our data suggest that increased autophagy may be a potential mechanism by which simvastatin improves skeletal muscle health and function in muscular dystrophy.

View Article: PubMed Central - PubMed

Affiliation: a Department of Physiology and Biophysics , University of Washington , Seattle , WA.

ABSTRACT
Autophagy has recently emerged as an important cellular process for the maintenance of skeletal muscle health and function. Excessive autophagy can trigger muscle catabolism, leading to atrophy. In contrast, reduced autophagic flux is a characteristic of several muscle diseases, including Duchenne muscular dystrophy, the most common and severe inherited muscle disorder. Recent evidence demonstrates that enhanced reactive oxygen species (ROS) production by CYBB/NOX2 impairs autophagy in muscles from the dmd/mdx mouse, a genetic model of Duchenne muscular dystrophy. Statins decrease CYBB/NOX2 expression and activity and stimulate autophagy in skeletal muscle. Therefore, we treated dmd/mdx mice with simvastatin and showed decreased CYBB/NOX2-mediated oxidative stress and enhanced autophagy induction. This was accompanied by reduced muscle damage, inflammation and fibrosis, and increased muscle force production. Our data suggest that increased autophagy may be a potential mechanism by which simvastatin improves skeletal muscle health and function in muscular dystrophy.

No MeSH data available.


Related in: MedlinePlus