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Skeletal Muscle Mitochondrial Oxidative Phosphorylation Function in Idiopathic Pulmonary Arterial Hypertension - In Vivo and In Vitro Study
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A2443 - Skeletal Muscle Mitochondrial Oxidative Phosphorylation Function in Idiopathic Pulmonary Arterial Hypertension - In Vivo and In Vitro Study
Author Block: S. Sithamparanathan1, M. C. Rocha2, J. D. Parikh3, K. A. Rygiel4, G. Falkous2, J. Grady2, K. G. Hollingsworth3, M. I. Trenell3, R. W. Taylor2, D. M. Turnbull2, G. S. Gorman2, P. Corris5; 1Respiratory, Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, United Kingdom, 2Institute of Neuroscience, Newcastle upon Tyne, United Kingdom, 3Institute of Cellular Medicine, Newcastle upon Tyne, United Kingdom, 4Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle upon Tyne, United Kingdom, 5Respiratory, Freeman Hospital, Newcastle, United Kingdom.
Rationale:
Skeletal muscle dysfunction has been observed in idiopathic pulmonary arterial hypertension (IPAH). The aim of the present study was investigate whether impaired exercise capacity observed in patients with IPAH is due to a primary mitochondrial oxidative phosphorylation (OXPHOS) dysfunction in skeletal muscle.
Methods:
Nine clinically stable participants with IPAH underwent cardiopulmonary exercise testing, in vivo and in vitro assessment of mitochondrial function by 31P-magnetic resonance spectroscopy (31P-MRS) and laboratory muscle biopsy analysis. OXPHOS function in muscle biopsy was assessed using histochemistry and quadruple immunofluorescence.
Results:
Compared to reference control values,[6] six participants who underwent 31P-MRS scans, exhibited higher phosphocreatine recovery time kinetics (PCr t1/2) (40.0 ± 8.8 vs 27.2 ± 7.1 seconds, p = 0.013) and achieved lower minimum pH values (6.85 ± 0.10 vs 7.00 ± 0.02 , p = 0.001), but had normal ADP recovery kinetics ( 25.5 ± 7.1 vs 20.9 ± 5.1 seconds, p = 0.228), rest pH (7.03 ± 0.02 vs 7.03 ± 0.04, p = 0.573) and end pH (7.02 ± 0.04 vs 7.02 ± 0.02, p = 0.573).
The COX/SDH histochemical assay, which allows detection of enzymatic activity of succinate dehydrogenase (SDH) and cytochrome c oxidase (COX), did not reveal any respiratory-deficient myofibres in patients. This was also supported by modified Gomori trichrome staining that demonstrated absence of any ragged-red fibres, otherwise commonly found in primary mitochondrial myopathies. In order to corroborate our findings, quadruple immunofluorescence to assess abundance of selected protein subunits of complex I and IV of the mitochondrial respiratory chain was subsequently undertaken. We compared the results to skeletal muscle biopsy samples of two healthy normal controls and a patient with genetically-defined mitochondrial DNA disease, as positive control. These demonstrated normal levels (within 3 standard deviations) of complex I and IV in all nine muscle samples obtained from IPAH patients comparative to normal healthy controls.
Conclusions:
Our findings suggest that there is no primary mitochondrial OXPHOS dysfunction, but raises the possibility of impaired oxygen delivery to the mitochondria therefore affecting skeletal muscle bioenergetics during exercise.
Author Block: S. Sithamparanathan1, M. C. Rocha2, J. D. Parikh3, K. A. Rygiel4, G. Falkous2, J. Grady2, K. G. Hollingsworth3, M. I. Trenell3, R. W. Taylor2, D. M. Turnbull2, G. S. Gorman2, P. Corris5; 1Respiratory, Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, United Kingdom, 2Institute of Neuroscience, Newcastle upon Tyne, United Kingdom, 3Institute of Cellular Medicine, Newcastle upon Tyne, United Kingdom, 4Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle upon Tyne, United Kingdom, 5Respiratory, Freeman Hospital, Newcastle, United Kingdom.
Rationale:
Skeletal muscle dysfunction has been observed in idiopathic pulmonary arterial hypertension (IPAH). The aim of the present study was investigate whether impaired exercise capacity observed in patients with IPAH is due to a primary mitochondrial oxidative phosphorylation (OXPHOS) dysfunction in skeletal muscle.
Methods:
Nine clinically stable participants with IPAH underwent cardiopulmonary exercise testing, in vivo and in vitro assessment of mitochondrial function by 31P-magnetic resonance spectroscopy (31P-MRS) and laboratory muscle biopsy analysis. OXPHOS function in muscle biopsy was assessed using histochemistry and quadruple immunofluorescence.
Results:
Compared to reference control values,[6] six participants who underwent 31P-MRS scans, exhibited higher phosphocreatine recovery time kinetics (PCr t1/2) (40.0 ± 8.8 vs 27.2 ± 7.1 seconds, p = 0.013) and achieved lower minimum pH values (6.85 ± 0.10 vs 7.00 ± 0.02 , p = 0.001), but had normal ADP recovery kinetics ( 25.5 ± 7.1 vs 20.9 ± 5.1 seconds, p = 0.228), rest pH (7.03 ± 0.02 vs 7.03 ± 0.04, p = 0.573) and end pH (7.02 ± 0.04 vs 7.02 ± 0.02, p = 0.573).
The COX/SDH histochemical assay, which allows detection of enzymatic activity of succinate dehydrogenase (SDH) and cytochrome c oxidase (COX), did not reveal any respiratory-deficient myofibres in patients. This was also supported by modified Gomori trichrome staining that demonstrated absence of any ragged-red fibres, otherwise commonly found in primary mitochondrial myopathies. In order to corroborate our findings, quadruple immunofluorescence to assess abundance of selected protein subunits of complex I and IV of the mitochondrial respiratory chain was subsequently undertaken. We compared the results to skeletal muscle biopsy samples of two healthy normal controls and a patient with genetically-defined mitochondrial DNA disease, as positive control. These demonstrated normal levels (within 3 standard deviations) of complex I and IV in all nine muscle samples obtained from IPAH patients comparative to normal healthy controls.
Conclusions:
Our findings suggest that there is no primary mitochondrial OXPHOS dysfunction, but raises the possibility of impaired oxygen delivery to the mitochondria therefore affecting skeletal muscle bioenergetics during exercise.
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