Summary of project PR000460
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000460. The data can be accessed directly via it's Project DOI: 10.21228/M8M027 This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR000460 |
| Project DOI: | doi: 10.21228/M8M027 |
| Project Title: | The dystrophic muscle metabolome: effects of exercise and NO donor therapy |
| Project Summary: | In Duchenne and Becker muscular dystrophy (DMD, BMD), loss of the cytoskeletal protein dystrophin weakens the sarcolemma and disrupts cellular signaling, rendering the diseased muscles susceptible to contractioninduced damage. We and others have shown that loss of neuronal nitric oxide synthase (nNOSμ) from the sarcolemma of dystrophin-deficient muscle causes functional muscle ischemia during exercise due to unopposed sympathetic vasoconstriction, thereby exacerbating fatigue and injury of the diseased muscles. Genetic and pharmacologic strategies targeting nNOSμ-NO signaling ameliorate functional muscle ischemia, as well as many other features of the dystrophic phenotype in the mdx mouse model of DMD/BMD. These findings suggest that the therapeutic benefit of NO likely extends beyond its vascular effects. A growing body of evidence indicates that NO directly influences muscle metabolism through effects on glucose transport as well as mitochondrial biogenesis and function. Both nNOS-/- mice and mdx mice exhibit muscle mitochondrial dysfunction, decreased resistance to fatigue, and exercise-induced muscle injury, suggesting a causal role of nNOSμ-NO deficiency. However, the specific metabolic changes resulting from reduced NO signaling that might render dystrophic muscle susceptible to fatigue and use-dependent injury remain poorly defined. Therefore, the goal of this pilot metabolomics study is to identify the unique biochemical profiles of skeletal and cardiac muscles of mdx mice to gain further mechanistic insight into the pathophysiological role of NO deficiency in muscular dystrophy. In Aim 1, we will characterize the skeletal and cardiac muscle metabolomes of mdx and nNOS-/- mice at rest and following a single bout of treadmill exercise with the goal of discovering common metabolic signatures caused by loss of NO signaling. In Aim 2, we will evaluate the potential of a NO donor drug that is under development as a therapeutic for DMD/BMD to improve the skeletal and cardiac muscle metabolomes in mdx mice. As a result of this pilot study, we hope to gain new understanding of the metabolic derangements in dystrophin-deficient muscle, insight into the therapeutic effects of NO replacement, and to identify new pathogenic mechanisms and putative therapeutic targets that will form the basis of future grant applications. |
| Institute: | Mayo Clinic |
| Last Name: | Thomas |
| First Name: | Gail |
| Address: | Penn State Hershey Heart and Vascular Institute Penn State College of Medicine 500 University Drive, MC H047 Hershey, PA 17033 |
| Email: | gthomas4@hmc.psu.edu |
| Phone: | 717-531-0003, ext. 287087 |
Summary of all studies in project PR000460
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST000645 | Effects of Exercise on Dystrophic Mouse Muscle Amino Acids (part I) | Mus musculus | Mayo Clinic | MS | 2019-07-17 | 1 | 30 | Not available |
| ST000646 | Effects of Exercise on Dystrophic Mouse Muscle TCA Cycle (part II) | Mus musculus | Mayo Clinic | MS | 2019-07-17 | 1 | 30 | Not available |
| ST000647 | Effects of Exercise on Dystrophic Mouse Muscle Non-Esterified Fatty Acids (part III) | Mus musculus | Mayo Clinic | MS | 2019-07-17 | 1 | 30 | Not available |
| ST000648 | Effects of NO Donor Therapy on the Dystrophic Mouse Muscle Amino Acids (part IV) | Mus musculus | Mayo Clinic | MS | 2019-07-17 | 1 | 30 | Not available |
| ST000649 | Effects of NO Donor Therapy on the Dystrophic Mouse Muscle Non-Esterified Fatty Acids (part V) | Mus musculus | Mayo Clinic | MS | 2019-07-17 | 1 | 30 | Not available |
| ST000650 | Effects of NO Donor Therapy on the Dystrophic Mouse Muscle TCA Cycle (part VI) | Mus musculus | Mayo Clinic | MS | 2019-07-17 | 1 | 30 | Not available |
| ST000651 | Effects of NO Donor Therapy on the Dystrophic Mouse Heart Metabolome (part VII) | Mus musculus | Mayo Clinic | MS* | 2019-07-17 | 1 | 240 | Uploaded data (3.2M) |
| ST000652 | Effects of NO Donor Therapy on the Dystrophic Mouse Quadricep Metabolome (part VIII) | Mus musculus | Mayo Clinic | MS* | 2019-07-17 | 1 | 240 | Uploaded data (1.7M) |
| ST000653 | Effects of Exercise on Dystrophic Mouse Heart Meabolome (part IX) | Mus musculus | Mayo Clinic | MS* | 2019-07-17 | 1 | 240 | Uploaded data (1.6M) |
| ST000654 | Effects of Exercise on Dystrophic Mouse Quadricep Meabolome (part X) | Mus musculus | Mayo Clinic | MS* | 2019-07-17 | 1 | 226 | Uploaded data (1.8M) |
