Skeletal Muscle Dysfunction in Idiopathic Pulmonary Arterial Hypertension
| Autor: | John Granton, Jane Batt, Alexandra Bain, Samar Shadly Ahmed, Judy Correa |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Adult
Male Pulmonary and Respiratory Medicine medicine.medical_specialty Vastus lateralis muscle Hypertension Pulmonary Ubiquitin-Protein Ligases Clinical Biochemistry Muscle Proteins Motor Activity Biology Mitochondrion Mitochondrial Membrane Transport Proteins GTP Phosphohydrolases Quadriceps Muscle Muscle hypertrophy Mitochondrial Proteins Tripartite Motif Proteins Internal medicine medicine Humans Familial Primary Pulmonary Hypertension Phosphorylation Exercise Molecular Biology SKP Cullin F-Box Protein Ligases Ryanodine receptor Ribosomal Protein S6 Kinases 70-kDa Skeletal muscle Ryanodine Receptor Calcium Release Channel Mitochondrial Turnover Cell Biology Anatomy Muscle atrophy Mitochondria Muscular Atrophy medicine.anatomical_structure Endocrinology Mitochondrial biogenesis Muscle Fibers Fast-Twitch Quality of Life Female medicine.symptom Proto-Oncogene Proteins c-akt Anaerobic exercise Signal Transduction |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 50:74-86 |
| ISSN: | 1535-4989 1044-1549 |
| Popis: | Despite improvements in survival with disease-targeted therapies, the majority of patients with pulmonary arterial hypertension (PAH) have persistent exercise intolerance that results from impaired cardiac function and skeletal muscle dysfunction. Our intent was to understand the molecular mechanisms mediating skeletal muscle dysfunction in PAH. A total of 12 patients with PAH and 10 matched control subjects were assessed. Patients with PAH demonstrated diminished exercise capacity (lower oxygen uptake max, lower anaerobic threshold and higher minute ventilation/CO2) compared with control subjects. Quadriceps muscle cross-sectional area was significantly smaller in patients with PAH. The vastus lateralis muscle was biopsied to enable muscle fiber morphometric assessment and to determine expression levels/activation of proteins regulating (1) muscle mass, (2) mitochondria biogenesis and shaping machinery, and (3) excitation-contraction coupling. Patients with PAH demonstrated a decreased type I/type II muscle fiber ratio, with a smaller cross-sectional area in the type I fibers. Diminished AKT and p70S6 kinase phosphorylation, with increased atrogin-1 and muscle RING-finger protein-1 transcript levels, were evident in the PAH muscle, suggesting engagement of cellular signaling networks stimulating ubiquitin-proteasome-mediated proteolysis of muscle, with concurrent depression of networks mediating muscle hypertrophy. Although there were no differences in expression/activation of proteins associated with mitochondrial biogenesis or fission (MTCO2 [cytochrome C oxidase subunit II]/succinate dehydrogenase flavoprotein subunit A, mitochondrial transcription factor A, nuclear respiratory factor-1/dynamin-related protein 1 phosphorylation), protein levels of a positive regulator of mitochondrial fusion, Mitofusin2, were significantly lower in patients with PAH. Patients with PAH demonstrated increased phosphorylation of ryanodine receptor 1 receptors, suggesting that altered sarcoplasmic reticulum Ca(++) sequestration may impair excitation-contraction coupling in the PAH muscle. These data suggest that muscle dysfunction in PAH results from a combination of muscle atrophy and intrinsically impaired contractility. |
| Databáze: | OpenAIRE |
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