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GRMD cardiac and skeletal muscle metabolism gene profiles are distinct
Larry W Markham1,2, Candice L Brinkmeyer-Langford3, Jonathan H Soslow2
1Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 2200 Pierce Avenue, 359A Preston Research Building, Nashville, TN, 37232, USA.
Insights
Duchenne muscular dystrophy (DMD) in dogs shows delayed cardiac dysfunction due to distinct metabolic changes. Skeletal muscle faces a "metabolic crisis," while cardiac muscle shows altered nucleotide metabolism and neuromuscular junction pathways.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Duchenne muscular dystrophy (DMD) results from DMD gene mutations affecting dystrophin.
- Understanding the delayed cardiac vs. skeletal muscle dysfunction in DMD remains a challenge.
Purpose of the Study:
- Investigate the molecular mechanisms behind differential muscle dysfunction in DMD.
- Analyze cardiac and skeletal muscle tissue in a Golden Retriever Muscular Dystrophy (GRMD) dog model.
Main Methods:
- Tissue microarrays from GRMD dogs and controls at various ages (6, 12, 47-93 months) were analyzed.
- Transcriptional profiles and functional enrichments in cardiac and skeletal muscle were compared.
Main Results:
- GRMD dogs displayed tissue- and age-specific gene expression.
- Skeletal muscle showed a "metabolic crisis" with downregulated energy production molecules (TCA cycle, electron transport).
- Cardiac muscle genes were enriched in nucleotide metabolism and neuromuscular junction pathways.
Conclusions:
- Differential metabolic dysfunction contributes to distinct skeletal and cardiac muscle pathologies in DMD.
- GRMD dogs serve as a valuable model for studying DMD pathogenesis.
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.