Investigation of muscle bioenergetics in the Marfan syndrome indicates reduced metabolic efficiency.

BACKGROUND: The Marfan syndrome is an inherited multisystem disorder caused by mutations in fibrillin 1, with cardiovascular involvement being the most important feature of the phenoptype. Affected individuals have impaired flow-mediated dilatation (FMD) of large arteries of a similar severity to patients with chronic heart failure (CHF). AIMS: Skeletal muscle bioenergetics were studied in patients with the Marfan syndrome in order to evaluate the impact of impaired flow-mediated dilatation on skeletal muscle metabolism. Skeletal muscle metabolism is abnormal in CHF and the aetiology is unclear. METHODS: Thirteen patients and 12 controls were studied by phosphorus Magnetic Resonance spectroscopy of the calf muscle using an incremental exercise protocol and by Magnetic Resonance imaging. RESULTS: Metabolic variables measured at rest were normal in Marfan patients. For a similar total work output measured at end of the standardized incremental exercise, the total rate of energy consumption (EC) was significantly increased in patients (21.2 +/- 2.3 mM ATP/min/W vs 13.6 +/- 1.4 mM ATP/min/W in controls). Similarly, both PCr and pH time-dependent changes were significantly different between groups. The absolute contributions of aerobic and glycolytic pathways to energy production were significantly higher in patients whereas they were similar when expressed relative to EC. CONCLUSIONS: The higher EC measured in patients with Marfan syndrome was supported by both oxidative and anaerobic metabolic pathways, thereby suggesting a decrease in muscle efficiency and/or muscle mass, as previously described in other diseases affecting skeletal muscle function such as heart failure and peripheral vascular disease.

Bovine model of Marfan syndrome results from an amino acid change (c.3598G > A, p.E1200K) in a calcium-binding epidermal growth factor-like domain of fibrillin-1.

Marfan Syndrome (MFS) is an autosomal dominant disorder caused by mutations in the fibrillin-1 gene (FBN1). Several calves, all sired by a phenotypically normal bull, were found to exhibit the major clinical and pathological characteristics of human MFS (aortic dissection, joint laxity, lens dislocation), and were recognized as potential models of the human disease. In this study, Fbn1 cDNA from affected animals was sequenced and a heterozygous c.3598G > A transition was detected in exon 29, which predicted the substitution of an evolutionarily conserved glutamic acid by lysine at position 1200 (p.E1200K). This residue is part of a calcium-binding epidermal growth factor-like (cbEGF-like) module, a domain that is frequently altered in human MFS. Analysis of genomic DNA from the original bull's sperm showed that less than 20% of the sperm harbored the mutation, consistent with the presence of germline mosaicism. This study validates the use of these animals as models of human MFS. These cows will be valuable for investigations into the molecular pathogenesis of MFS, and may lead to better therapeutic testing and evaluation of human Marfan patients.

Interleukin-1beta in plasma and synovial fluid in relation to radiographic changes in arthritic temporomandibular joints.

The aim of this study was to investigate the level of the cytokine IL-1beta in plasma and temporomandibular joint (TMJ) synovial fluid of patients with arthropathies, and to study the relation between IL-1beta levels of synovial fluid and plasma as well as radiographic changes of the TMJ. 31 patients with general disease, 14 with rheumatoid arthritis (RA) and 17 with various arthritides were included in the study. Synovial fluid and blood samples were collected, and an individualized tomography of the TMJ was performed. Detectable levels of IL-1beta were found in 5 out of 39 synovial fluids and in 10 out of 27 plasma samples. The presence of IL-1beta in both plasma and synovial fluid was more frequent in RA patients than in the non-RA group. The extension of radiographic erosion was significantly greater in joints with IL-1beta than in those without. Both the extension of erosion and grade of radiographic changes of the TMJ were greater in patients with detectable IL-1beta level of plasma than in patients without. Our study indicates that presence of IL-1beta in plasma and synovial fluid is related to radiographic changes of the TMJ.