Rescue of dystrophic skeletal muscle by PGC-1α involves restored expression of dystrophin-associated protein complex components and satellite cell signaling

Hollinger, Katrin; Gardan-Salmon, Delphine; Santana, Connie; Rice, Drance; Snella, Elizabeth M.; Selsby, Joshua T.

doi:10.1152/ajpregu.00221.2012

Cited by 48 publications

(79 citation statements)

References 66 publications

(99 reference statements)

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“…One approach to this target is gene therapy. Recent reports have suggested that viral or plasmid delivery of PGC-1α post-natally can improve muscle function in mdx mice [32,63]. Our data support this conclusion, and show that PGC-1α expression specifically in myotubes likely mediates this protection.…”

Section: Discussionsupporting

confidence: 89%

Post-natal induction of PGC-1α protects against severe muscle dystrophy independently of utrophin

et al. 2014

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BackgroundDuchenne muscle dystrophy (DMD) afflicts 1 million boys in the US and has few effective treatments. Constitutive transgenic expression of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α improves skeletal muscle function in the murine “mdx” model of DMD, but how this occurs, or whether it can occur post-natally, is not known. The leading mechanistic hypotheses for the benefits conferred by PGC-1α include the induction of utrophin, a dystrophin homolog, and/or induction and stabilization of the neuromuscular junction.MethodsThe effects of transgenic overexpression of PGC-1β, a homolog of PGC-1α in mdx mice was examined using different assays of skeletal muscle structure and function. To formally test the hypothesis that PGC-1α confers benefit in mdx mice by induction of utrophin and stabilization of neuromuscular junction, PGC-1α transgenic animals were crossed with the dystrophin utrophin double knock out (mdx/utrn-/-) mice, a more severe dystrophic model. Finally, we also examined the effect of post-natal induction of skeletal muscle-specific PGC-1α overexpression on muscle structure and function in mdx mice.ResultsWe show here that PGC-1β does not induce utrophin or other neuromuscular genes when transgenically expressed in mouse skeletal muscle. Surprisingly, however, PGC-1β transgenesis protects as efficaciously as PGC-1α against muscle degeneration in dystrophin-deficient (mdx) mice, suggesting that alternate mechanisms of protection exist. When PGC-1α is overexpressed in mdx/utrn-/- mice, we find that PGC-1α dramatically ameliorates muscle damage even in the absence of utrophin. Finally, we also used inducible skeletal muscle-specific PGC-1α overexpression to show that PGC-1α can protect against dystrophy even if activated post-natally, a more plausible therapeutic option.ConclusionsThese data demonstrate that PGC-1α can improve muscle dystrophy post-natally, highlighting its therapeutic potential. The data also show that PGC-1α is equally protective in the more severely affected mdx/utrn-/- mice, which more closely recapitulates the aggressive progression of muscle damage seen in DMD patients. The data also identify PGC-1β as a novel potential target, equally efficacious in protecting against muscle dystrophy. Finally, the data also show that PGC-1α and PGC-1β protect against dystrophy independently of utrophin or of induction of the neuromuscular junction, indicating the existence of other mechanisms.

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Section: Discussionsupporting

confidence: 89%

Post-natal induction of PGC-1α protects against severe muscle dystrophy independently of utrophin

et al. 2014

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“…Autophagy emerges then as an essential process for the clearance of defunct cellular organelles and a continued inhibition of autophagy exaggerates dystrophic phenotype (Hindi et al, 2014). The beneficial effects of activating autophagy in mdx mice have been also confirmed by overexpressing peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1a), a transcriptional coactivator, which is a powerful mediator of muscle plasticity (Hollinger et al, 2013) and by pharmacological treatment with an agonist drug against the energy sensor AMPK, i.e., 5-aminoimidazole-4-carboxamide-1-β- d -ribofuranoside (AICAR) (Pauly et al, 2012). In particular, AICAR treatment led to a significant activation of the autophagy, as indicated by the characteristic biochemical changes of increased lipidated LC3 content, an upregulation of other prototypical autophagy-associated proteins, and to significant improvements in both muscle structure and maximum force-generating capacity (Pauly et al, 2012).…”

Section: Deregulation Of Autophagy In Duchenne Muscular Dystrophymentioning

confidence: 99%

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

Palma

Perrotta

Pellegrino

et al. 2014

Front. Aging Neurosci.

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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.

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“…; Hollinger et al . ; Hollinger & Selsby, ). In many regards this approach mimics the effects of endurance exercise, which is controversial in DMD patients due to the potential for increased injury (Carter et al .…”

Section: Introductionmentioning

confidence: 99%

Oral quercetin administration transiently protects respiratory function in dystrophin‐deficient mice

Selsby

Ballmann

Spaulding

et al. 2016

The Journal of Physiology

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Key pointr PGC-1α pathway activation has been shown to decrease disease severity and can be driven by quercetin.r Oral quercetin supplementation protected respiratory function for 4-6 months during a 12 month dosing regimen.r This transient protection was probably due to a failure to sustain elevated SIRT1 activity and downstream PGC-1α signalling.r Quercetin supplementation may be a beneficial treatment as part of a cocktail provided continued SIRT1 activity elevation is achieved.Abstract Duchenne muscular dystrophy (DMD) impacts 1 : 3500 boys and leads to muscle dysfunction culminating in death due to respiratory or cardiac failure. There is an urgent need for effective therapies with the potential for immediate application for this patient population. Quercetin, a flavonoid with an outstanding safety profile, may provide therapeutic relief to DMD patients as the wait for additional therapies continues. This study evaluated the capacity of orally administered quercetin (0.2%) in 2 month old mdx mice to improve respiratory function and end-point functional and histological outcomes in the diaphragm following 12 months of treatment. Respiratory function was protected for the first 4-6 months of treatment but appeared to become insensitive to quercetin thereafter. Consistent with this, end-point functional measures were decreased and histopathological measures were more severe in dystrophic muscle compared to C57 and similar between control-fed and quercetin-fed mdx mice. To better understand the transient nature of improved respiratory function, we measured PGC-1α pathway activity, which is suggested to be up-regulated by quercetin supplementation. This pathway was largely suppressed in dystrophic muscle compared to healthy muscle, and at the 14 month time point dietary quercetin enrichment did not increase expression of downstream effectors. These data support the efficacy of quercetin as an intervention for DMD in skeletal muscle, and also indicate the development of age-dependent quercetin insensitivity when continued supplementation fails to drive the PGC-1α pathway. Continued study is needed to determine if this is related to disease severity, age or other factors.

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Rescue of dystrophic skeletal muscle by PGC-1α involves restored expression of dystrophin-associated protein complex components and satellite cell signaling

Cited by 48 publications

References 66 publications

Post-natal induction of PGC-1α protects against severe muscle dystrophy independently of utrophin

Post-natal induction of PGC-1α protects against severe muscle dystrophy independently of utrophin

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

Oral quercetin administration transiently protects respiratory function in dystrophin‐deficient mice

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