Cholesterol absorption blocker ezetimibe prevents muscle wasting in severe dysferlin‐deficient and mdx mice

Duchenne muscular dystrophy (DMD) is a genetic disease characterized by muscle wasting and chronic inflammation, leading to impaired satellite cells (SCs) function and exhaustion of their regenerative capacity. We previously showed that lack of PKCθ in mdx mice, a mouse model of DMD, reduces muscle wasting and inflammation, and improves muscle regeneration and performance at early stages of the disease. In this study, we show that muscle regeneration is boosted, and fibrosis reduced in mdxθ−/− mice, even at advanced stages of the disease. This phenotype was associated with a higher number of Pax7 positive cells in mdxθ−/− muscle compared with mdx muscle, during the progression of the disease. Moreover, the expression level of Pax7 and Notch1, the pivotal regulators of SCs self-renewal, were upregulated in SCs isolated from mdxθ−/− muscle compared with mdx derived SCs. Likewise, the expression of the Notch ligands Delta1 and Jagged1 was higher in mdxθ−/− muscle compared with mdx. The expression level of Delta1 and Jagged1 was also higher in PKCθ−/− muscle compared with WT muscle following acute injury. In addition, lack of PKCθ prolonged the survival and sustained the differentiation of transplanted myogenic progenitors. Overall, our results suggest that lack of PKCθ promotes muscle repair in dystrophic mice, supporting stem cells survival and maintenance through increased Delta-Notch signaling.

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SERCA1 overexpression minimizes skeletal muscle damage in dystrophic mouse models

AJP Cell Physiology ◽

10.1152/ajpcell.00341.2014 ◽

2015 ◽

Vol 308 (9) ◽

pp. C699-C709 ◽

Cited By ~ 23

Author(s):

Davi A. G. Mázala ◽

Stephen J. P. Pratt ◽

Dapeng Chen ◽

Jeffery D. Molkentin ◽

Richard M. Lovering ◽

...

Keyword(s):

Mouse Model ◽

Muscle Damage ◽

Muscle Wasting ◽

Mdx Mice ◽

Functional Impairments ◽

Wild Type ◽

Skeletal Muscle Damage ◽

Threefold Increase ◽

Intracellular Ca ◽

Cellular Markers

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting secondary to repeated muscle damage and inadequate repair. Elevations in intracellular free Ca2+ have been implicated in disease progression, and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 1 (SERCA1) overexpression has been shown to ameliorate the dystrophic phenotype in mdx mice. The purpose of this study was to assess the effects of SERCA1 overexpression in the more severe mdx/Utr−/− mouse model of DMD. Mice overexpressing SERCA1 were crossed with mdx/Utr+/− mice to generate mdx/Utr−/−/+SERCA1 mice and compared with wild-type (WT), WT/+SERCA1, mdx/+SERCA1, and genotype controls. Mice were assessed at ∼12 wk of age for changes in Ca2+ handling, muscle mass, quadriceps torque, markers of muscle damage, and response to repeated eccentric contractions. SERCA1-overexpressing mice had a two- to threefold increase in maximal sarcoplasmic reticulum Ca2+-ATPase activity compared with WT which was associated with normalization in body mass for both mdx/+SERCA1 and mdx/Utr−/−/+SERCA1. Torque deficit in the quadriceps after eccentric injury was 2.7-fold greater in mdx/Utr−/− vs. WT mice, but only 1.5-fold greater in mdx/Utr−/−/+SERCA1 vs. WT mice, an attenuation of 44%. Markers of muscle damage (% centrally nucleated fibers, necrotic area, and serum creatine kinase levels) were higher in both mdx and mdx/Utr−/− vs. WT, and all were attenuated by overexpression of SERCA1. These data indicate that SERCA1 overexpression ameliorates functional impairments and cellular markers of damage in a more severe mouse model of DMD. These findings support targeting intracellular Ca2+ control as a therapeutic approach for DMD.

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Complementary NAD+ Replacement Strategies Fail to Functionally Protect Dystrophin-Deficient Muscle

10.21203/rs.3.rs-28529/v1 ◽

2020 ◽

Author(s):

David Frederick ◽

Alan V. McDougal ◽

Melisa Semenas ◽

Johanna Vappiani ◽

Andrea Nuzzo ◽

...

Keyword(s):

Small Molecules ◽

Nicotinamide Adenine Dinucleotide ◽

Muscle Wasting ◽

Therapeutic Benefit ◽

Mdx Mice ◽

Molecular Phenotype ◽

Nicotinamide Riboside ◽

Adp Ribosyl Cyclase ◽

Molecular Phenotypes ◽

Muscle Damage Markers

Abstract Background Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder stemming from a loss of functional dystrophin. Current therapeutic options for DMD are limited, as small molecule modalities remain largely unable to lessen the incidence or mitigate the consequences of repetitive mechanical insults to the muscle during eccentric contractions (ECCs). Methods Using a metabolomics approach, we observed distinct and transient molecular phenotypes in muscles of dystrophin-deficient MDX mice subjected to ECCs. Among the most depleted metabolites was nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor suggested to protect muscle from structural and metabolic degeneration over time. We tested whether the MDX muscle NAD pool can be expanded for therapeutic benefit by providing a biosynthetic precursor, nicotinamide riboside, or specifically inhibiting the NAD-degrading activity of the ADP-ribosyl cyclase, CD38. Results Administering a novel, potent, and orally available CD38 antagonist to MDX mice successfully reverted a majority of the muscle metabolome toward the wildtype state, while supplementing nicotinamide riboside did not significantly affect the molecular phenotype of the muscle. However, neither strategy effectively lessened muscle damage markers or improved hindlimb strength following repeated rounds of eccentric challenge and recovery. Conclusions Intramuscular NAD depletion occurs rapidly after eccentic injury, with broad pleitropic effects on the molecular phenotype of the tissue. Currently available means of protecting or replenishing the muscle NAD pool via orally administered small molecules are insufficient to functionally restore dystrophin-deficient muscle.

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Complementary NAD+ Replacement Strategies Fail to Functionally Protect Dystrophin-Deficient Muscle

10.21203/rs.3.rs-28529/v2 ◽

2020 ◽

Author(s):

David Frederick ◽

Alan V. McDougal ◽

Melisa Semenas ◽

Johanna Vappiani ◽

Andrea Nuzzo ◽

...

Keyword(s):

Small Molecules ◽

Nicotinamide Adenine Dinucleotide ◽

Muscle Wasting ◽

Therapeutic Benefit ◽

Mdx Mice ◽

Molecular Phenotype ◽

Nicotinamide Riboside ◽

Adp Ribosyl Cyclase ◽

Molecular Phenotypes ◽

Muscle Damage Markers

Abstract Background Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder stemming from a loss of functional dystrophin. Current therapeutic options for DMD are limited, as small molecule modalities remain largely unable to lessen the incidence or mitigate the consequences of repetitive mechanical insults to the muscle during eccentric contractions (ECCs). Methods Using a metabolomics approach, we observed distinct and transient molecular phenotypes in muscles of dystrophin-deficient MDX mice subjected to ECCs. Among the most depleted metabolites was nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor suggested to protect muscle from structural and metabolic degeneration over time. We tested whether the MDX muscle NAD pool can be expanded for therapeutic benefit by providing a biosynthetic precursor, nicotinamide riboside, or specifically inhibiting the NAD-degrading activity of the ADP-ribosyl cyclase, CD38. Results Administering a novel, potent, and orally available CD38 antagonist to MDX mice successfully reverted a majority of the muscle metabolome toward the wildtype state, while supplementing nicotinamide riboside did not significantly affect the molecular phenotype of the muscle. However, neither strategy effectively lessened muscle damage markers or improved hindlimb strength following repeated rounds of eccentric challenge and recovery. Conclusions Intramuscular NAD depletion occurs rapidly after eccentic injury, with broad pleitropic effects on the molecular phenotype of the tissue. Currently available means of protecting or replenishing the muscle NAD pool via orally administered small molecules are insufficient to functionally restore dystrophin-deficient muscle.

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Fine structure of early degenerating myofibers in the tibialis anterior of young ‘MDX’ mouse

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010010367x ◽

1988 ◽

Vol 46 ◽

pp. 322-323

Author(s):

H.D. Geissinger ◽

C.K. McDonald-Taylor

Keyword(s):

Fine Structure ◽

Muscle Regeneration ◽

Tibialis Anterior ◽

Genetic Defect ◽

Mdx Mouse ◽

Mdx Mice ◽

Histopathological Changes ◽

Electron Microscopic ◽

Dystrophic Mouse ◽

Preliminary Study

A new strain of mice, which had arisen by mutation from a dystrophic mouse colony was designated ‘mdx’, because the genetic defect, which manifests itself in brief periods of muscle destruction followed by episodes of muscle regeneration appears to be X-linked. Further studies of histopathological changes in muscle from ‘mdx’ mice at the light microscopic or electron microscopic levels have been published, but only one preliminary study has been on the tibialis anterior (TA) of ‘mdx’ mice less than four weeks old. Lesions in the ‘mdx’ mice vary between different muscles, and centronucleation of fibers in all muscles studied so far appears to be especially prominent in older mice. Lesions in young ‘mdx’ mice have not been studied extensively, and the results appear to be at variance with one another. The degenerative and regenerative aspects of the lesions in the TA of 23 to 26-day-old ‘mdx’ mice appear to vary quantitatively.

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Regenerating myofibers in tibialis anterior muscles of young ‘MDX’ mice

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100127943 ◽

1987 ◽

Vol 45 ◽

pp. 726-727

Author(s):

H. D. Geissinge ◽

L.D. Rhodes

Keyword(s):

Muscular Dystrophy ◽

Mouse Model ◽

Tibialis Anterior ◽

Physiological Activity ◽

Mdx Mice ◽

Mode Of Inheritance

A recently discovered mouse model (‘mdx’) for muscular dystrophy in man may be of considerable interest, since the disease in ‘mdx’ mice is inherited by the same mode of inheritance (X-linked) as the human Duchenne (DMD) muscular dystrophy. Unlike DMD, which results in a situation in which the continual muscle destruction cannot keep up with abortive regenerative attempts of the musculature, and the sufferers of the disease die early, the disease in ‘mdx’ mice appears to be transient, and the mice do not die as a result of it. In fact, it has been reported that the severely damaged Tibialis anterior (TA) muscles of ‘mdx’ mice seem to display exceptionally good regenerative powers at 4-6 weeks, so much so, that these muscles are able to regenerate spontaneously up to their previous levels of physiological activity.

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The ubiquitin–proteasome system and skeletal muscle wasting

Essays in Biochemistry ◽

10.1042/bse0410173 ◽

2005 ◽

Vol 41 ◽

pp. 173-186 ◽

Cited By ~ 110

Author(s):

Didier Attaix ◽

Sophie Ventadour ◽

Audrey Codran ◽

Daniel Béchet ◽

Daniel Taillandier ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Wasting ◽

Proteolytic Enzymes ◽

Cathepsin L ◽

Ubiquitin Proteasome System ◽

Complete Breakdown ◽

Skeletal Muscle Proteins ◽

Ubiquitin Proteasome ◽

Tripeptidyl Peptidase Ii ◽

F Box Protein

The ubiquitin–proteasome system (UPS) is believed to degrade the major contractile skeletal muscle proteins and plays a major role in muscle wasting. Different and multiple events in the ubiquitination, deubiquitination and proteolytic machineries are responsible for the activation of the system and subsequent muscle wasting. However, other proteolytic enzymes act upstream (possibly m-calpain, cathepsin L, and/or caspase 3) and downstream (tripeptidyl-peptidase II and aminopeptidases) of the UPS, for the complete breakdown of the myofibrillar proteins into free amino acids. Recent studies have identified a few critical proteins that seem necessary for muscle wasting {i.e. the MAFbx (muscle atrophy F-box protein, also called atrogin-1) and MuRF-1 [muscle-specific RING (really interesting new gene) finger 1] ubiquitin–protein ligases}. The characterization of their signalling pathways is leading to new pharmacological approaches that can be useful to block or partially prevent muscle wasting in human patients.

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