PPARδ modulation rescues mitochondrial fatty acid oxidation defects in the mdx model of muscular dystrophy

Bell, Eric L.; Shine, Robert W.; Dwyer, Peter; Olson, Lyndsay; Truong, Jennifer; Fredenburg, Ross A.; Goddeeris, Matthew M.; Stickens, Dominique; Tozzo, Effie

doi:10.1016/j.mito.2018.02.006

Cited by 15 publications

(18 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Percival et al reported a reduction in the density of the subsarcolemmal mitochondria pool in mdx TA muscle(80), and mdx-derived myoblasts contain fewer mitochondria than their WT counterparts(81), consistent with this hypothesis.Upstream regulator analysis identified multiple master regulators of mitochondrial biogenesis as being perturbed in dystrophic muscle. These included the peroxisome proliferator activated receptor family members: PPARA, PPARG, and PPARD, their associated transcriptional coactivators: PPARGC1A (PGC-1α), and PPARGC1B (PGC-1β), and the mitochondria-specific transcription factor TFAM(Figure 4, S10C, S12).…”

mentioning

confidence: 76%

“…Notably, many of the regulatory proteins identified above have been explored as potential targets for pharmacological manipulation (Figure 9). For example, PGC-1α gain-of-function and pharmacological activation of PPARD have been shown to be beneficial in the mdx mouse (98), and reverse mitochondrial defects in mdx myoblasts (81), respectively. Activation of AMPK and SIRT1 (by AICAR (99) and resveratrol (100) respectively) has been shown to attenuate pathology in the mdx mouse, also a likely consequence of PGC-1α up-regulation.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mutation-independent Proteomic Signatures of Pathological Progression in Murine Models of Duchenne Muscular Dystrophy

Tle.

Johansson

Hanson

et al. 2020

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

The absence of the dystrophin protein in Duchenne muscular dystrophy (DMD) results in myofiber fragility and a plethora of downstream secondary pathologies. While a variety of experimental therapies are in development, achieving effective treatments for DMD remains exceptionally challenging, not least because the pathological consequences of dystrophin loss are incompletely understood. Here we have performed proteome profiling in tibialis anterior muscles from two murine DMD models (mdx and mdx52) at three ages (8, 16, and 80 weeks of age), all n=3. High-resolution isoelectric focusing liquid chromatography-tandem mass spectrometry (HiRIEF-LC-MS/MS) was used to quantify the expression of 4,974 proteins across all 27 samples. The two dystrophic models were found to be highly similar, whereas multiple proteins were differentially expressed relative to wild-type (C57BL/6) controls at each age. Furthermore, 1,795 proteins were differentially expressed when samples were pooled across ages and dystrophic strains. These included numerous proteins associated with the extracellular matrix and muscle function which have not been reported previously. Pathway analysis revealed multiple perturbed pathways and predicted upstream regulators which together are indicative of crosstalk between inflammatory, metabolic, and muscle growth pathways (e.g. TNF, INFγ, NF-κB, SIRT1, AMPK, PGC-1α, PPARs, ILK, and AKT/PI3K). Up-regulation of CAV3, MVP and PAK1 protein expression was validated in dystrophic muscle by Western blot. Furthermore, MVP was up-regulated during, but not required for, the differentiation of C2C12 myoblasts suggesting that this protein may affect muscle regeneration. This study provides novel insights into mutation-independent proteomic signatures characteristic of the dystrophic phenotype and its progression with aging.

show abstract

mentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Mutation-independent Proteomic Signatures of Pathological Progression in Murine Models of Duchenne Muscular Dystrophy

Tle.

Johansson

Hanson

et al. 2020

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

show abstract

“…PGC-1α is reported to be a direct target of PPARδ in the skeletal muscle (Phua et al, 2018). Recently, Bell et al (2019) showed that PPARδ improves mitochondrial function in the mdx mice. We also investigated the mitochondrial respiratory complexes (I, II, III, IV, and V), and similar to the PGC-1α and PPARδ results, the levels of these complexes were up regulated in exercise-trained-mdx mice treated with Tempol.…”

Section: Discussionmentioning

confidence: 99%

Oxidative Stress, Inflammation, and Activators of Mitochondrial Biogenesis: Tempol Targets in the Diaphragm Muscle of Exercise Trained-mdx Mice

et al. 2021

View full text Add to dashboard Cite

The mdx mouse phenotype aggravated by chronic exercise on a treadmill makes this murine model more reliable for the study of muscular dystrophy. Thus, to better assess the Tempol effect on dystrophic pathways, the analyses in this study were performed in the blood samples and diaphragm muscle from treadmill trained adult (7–11-weeks old) mdx animals. The mdx mice were divided into three groups: mdxSed, sedentary controls (n = 28); mdxEx, exercise-trained animals (n = 28); and mdxEx+T, exercise-trained animals with the Tempol treatment (n = 28). The results demonstrated that the Tempol treatment promoted muscle strength gain, prevented muscle damage, reduced the inflammatory process, oxidative stress, and angiogenesis regulator, and up regulated the activators of mitochondrial biogenesis. The main new findings of this study are that Tempol reduced the NF-κB and increased the PGC1-α and PPARδ levels in the exercise-trained-mdx mice, which are probably related to the ability of this antioxidant to scavenge excessive ROS. These results reinforce the use of Tempol as a potential therapeutic strategy in DMD.

show abstract

“…In fact, mitochondrial dysfunction has been shown to occur before the onset of myofiber necrosis, muscle wasting and myofibrillar defects [253]. Impaired substrate utilization and ATP synthesis have been reported in dystrophic mitochondria [254,255]. There occurs an uncoupling in the process of mitochondrial oxidative phosphorylation during the progression of muscular dystrophy [256,257].…”

Section: Mechanisms Of Subcellular Ca 2+ -Handling Abnormalities In Dystrophic Musclementioning

confidence: 99%

Role of molecular and metabolic defects in impaired performance of dystrophic skeletal muscles

Bhullar¹,

Nusier²,

Shah³

et al. 2021

Journal of Molecular and Clinical Medicine

View full text Add to dashboard Cite

PPARδ modulation rescues mitochondrial fatty acid oxidation defects in the mdx model of muscular dystrophy

Cited by 15 publications

References 26 publications

Mutation-independent Proteomic Signatures of Pathological Progression in Murine Models of Duchenne Muscular Dystrophy

Mutation-independent Proteomic Signatures of Pathological Progression in Murine Models of Duchenne Muscular Dystrophy

Oxidative Stress, Inflammation, and Activators of Mitochondrial Biogenesis: Tempol Targets in the Diaphragm Muscle of Exercise Trained-mdx Mice

Role of molecular and metabolic defects in impaired performance of dystrophic skeletal muscles

Contact Info

Product

Resources

About