GRMD cardiac and skeletal muscle metabolism gene profiles are distinct
Abstract Background Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, which codes for the dystrophin protein. While progress has been made in defining the molecular basis and pathogenesis of DMD, major gaps remain in understanding mechanisms that contribute to the marked dela...
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| Format: | Article |
| Language: | English |
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BMC
2017-04-01
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| Series: | BMC Medical Genomics |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12920-017-0257-2 |
| _version_ | 1829521781590851584 |
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| author | Larry W. Markham Candice L. Brinkmeyer-Langford Jonathan H. Soslow Manisha Gupte Douglas B. Sawyer Joe N. Kornegay Cristi L. Galindo |
| author_facet | Larry W. Markham Candice L. Brinkmeyer-Langford Jonathan H. Soslow Manisha Gupte Douglas B. Sawyer Joe N. Kornegay Cristi L. Galindo |
| author_sort | Larry W. Markham |
| collection | DOAJ |
| description | Abstract Background Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, which codes for the dystrophin protein. While progress has been made in defining the molecular basis and pathogenesis of DMD, major gaps remain in understanding mechanisms that contribute to the marked delay in cardiac compared to skeletal muscle dysfunction. Methods To address this question, we analyzed cardiac and skeletal muscle tissue microarrays from golden retriever muscular dystrophy (GRMD) dogs, a genetically and clinically homologous model for DMD. A total of 15 dogs, 3 each GRMD and controls at 6 and 12 months plus 3 older (47–93 months) GRMD dogs, were assessed. Results GRMD dogs exhibited tissue- and age-specific transcriptional profiles and enriched functions in skeletal but not cardiac muscle, consistent with a “metabolic crisis” seen with DMD microarray studies. Most notably, dozens of energy production-associated molecules, including all of the TCA cycle enzymes and multiple electron transport components, were down regulated. Glycolytic and glycolysis shunt pathway-associated enzymes, such as those of the anabolic pentose phosphate pathway, were also altered, in keeping with gene expression in other forms of muscle atrophy. On the other hand, GRMD cardiac muscle genes were enriched in nucleotide metabolism and pathways that are critical for neuromuscular junction maintenance, synaptic function and conduction. Conclusions These findings suggest differential metabolic dysfunction may contribute to distinct pathological phenotypes in skeletal and cardiac muscle. |
| first_indexed | 2024-12-16T15:21:21Z |
| format | Article |
| id | doaj.art-6f852da7d2e2474a811eccd2294ee126 |
| institution | Directory Open Access Journal |
| issn | 1755-8794 |
| language | English |
| last_indexed | 2024-12-16T15:21:21Z |
| publishDate | 2017-04-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medical Genomics |
| spelling | doaj.art-6f852da7d2e2474a811eccd2294ee1262022-12-21T22:26:37ZengBMCBMC Medical Genomics1755-87942017-04-0110111210.1186/s12920-017-0257-2GRMD cardiac and skeletal muscle metabolism gene profiles are distinctLarry W. Markham0Candice L. Brinkmeyer-Langford1Jonathan H. Soslow2Manisha Gupte3Douglas B. Sawyer4Joe N. Kornegay5Cristi L. Galindo6Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical CenterDepartment of Veterinary Integrative Biosciences, Texas A&M UniversityDepartment of Pediatrics, Division of Pediatric Cardiology, Vanderbilt University Medical CenterDepartment of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical CenterDepartment of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical CenterDepartment of Veterinary Integrative Biosciences, Texas A&M UniversityDepartment of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical CenterAbstract Background Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, which codes for the dystrophin protein. While progress has been made in defining the molecular basis and pathogenesis of DMD, major gaps remain in understanding mechanisms that contribute to the marked delay in cardiac compared to skeletal muscle dysfunction. Methods To address this question, we analyzed cardiac and skeletal muscle tissue microarrays from golden retriever muscular dystrophy (GRMD) dogs, a genetically and clinically homologous model for DMD. A total of 15 dogs, 3 each GRMD and controls at 6 and 12 months plus 3 older (47–93 months) GRMD dogs, were assessed. Results GRMD dogs exhibited tissue- and age-specific transcriptional profiles and enriched functions in skeletal but not cardiac muscle, consistent with a “metabolic crisis” seen with DMD microarray studies. Most notably, dozens of energy production-associated molecules, including all of the TCA cycle enzymes and multiple electron transport components, were down regulated. Glycolytic and glycolysis shunt pathway-associated enzymes, such as those of the anabolic pentose phosphate pathway, were also altered, in keeping with gene expression in other forms of muscle atrophy. On the other hand, GRMD cardiac muscle genes were enriched in nucleotide metabolism and pathways that are critical for neuromuscular junction maintenance, synaptic function and conduction. Conclusions These findings suggest differential metabolic dysfunction may contribute to distinct pathological phenotypes in skeletal and cardiac muscle.http://link.springer.com/article/10.1186/s12920-017-0257-2DuchenneBDNFMuscular dystrophyCardiacDystrophinMetabolism |
| spellingShingle | Larry W. Markham Candice L. Brinkmeyer-Langford Jonathan H. Soslow Manisha Gupte Douglas B. Sawyer Joe N. Kornegay Cristi L. Galindo GRMD cardiac and skeletal muscle metabolism gene profiles are distinct BMC Medical Genomics Duchenne BDNF Muscular dystrophy Cardiac Dystrophin Metabolism |
| title | GRMD cardiac and skeletal muscle metabolism gene profiles are distinct |
| title_full | GRMD cardiac and skeletal muscle metabolism gene profiles are distinct |
| title_fullStr | GRMD cardiac and skeletal muscle metabolism gene profiles are distinct |
| title_full_unstemmed | GRMD cardiac and skeletal muscle metabolism gene profiles are distinct |
| title_short | GRMD cardiac and skeletal muscle metabolism gene profiles are distinct |
| title_sort | grmd cardiac and skeletal muscle metabolism gene profiles are distinct |
| topic | Duchenne BDNF Muscular dystrophy Cardiac Dystrophin Metabolism |
| url | http://link.springer.com/article/10.1186/s12920-017-0257-2 |
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