Myoadenylate deaminase deficiency: absence of correlation with exercise intolerance in 452 muscle biopsies

Mercelis, R.; Martin, Jean‐Jacques; Barsy, Thierry de; Berghe, Georges

doi:10.1007/bf00314082

Cited by 31 publications

(14 citation statements)

References 23 publications

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“…19, 43, and 44 for reviews), and has been thought to cause AMP and ADP accumulation at high-energy demands, if the deficiency were great (49). The presence of AMPD deficiency is often associated with symptoms of exertional myalgia, such as muscle cramps and stiffness, as well as exaggerated fatigue and delayed muscle relaxation (11,49); however, deficits in muscle function are not necessarily independent of other myopathies (37). In fact, a large percentage of individuals with AMPD deficiency are asymptomatic.…”

Section: Discussionmentioning

confidence: 99%

“…4, E and F). This was apparent when the peak rate of force development is compared between the groups over the contractions where the largest functional differences were apparent between the groups (contractions [35][36][37][38][39][40]. In fact, an inverse relationship with increasing contraction frequency was apparent in the AK1 Ϫ/Ϫ group and not in the WT muscle (Fig.…”

Section: Contractile Function the Initial Peak Tetanic Tension Was Nmentioning

confidence: 99%

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Skeletal muscle contractile performance and ADP accumulation in adenylate kinase-deficient mice

Hancock¹,

Janssen²,

Terjung³

2005

American Journal of Physiology-Cell Physiology

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The production of AMP by adenylate kinase (AK) and subsequent deamination by AMP deaminase limits ADP accumulation during conditions of high-energy demand in skeletal muscle. The goal of this study was to investigate the consequences of AK deficiency (Ϫ/Ϫ) on adenine nucleotide management and whole muscle function at high-energy demands. To do this, we examined isometric tetanic contractile performance of the gastrocnemius-plantaris-soleus (GPS) muscle group in situ in AK1 Ϫ/Ϫ mice and wild-type (WT) controls over a range of contraction frequencies (30 -120 tetani/min). We found that AK1 Ϫ/Ϫ muscle exhibited a diminished inosine 5Ј-monophosphate formation rate (14% of WT) and an inordinate accumulation of ADP (ϳ1.5 mM) at the highest energy demands, compared with WT controls. AK-deficient muscle exhibited similar initial contractile performance (521 Ϯ 9 and 521 Ϯ 10 g tension in WT and AK1 Ϫ/Ϫ muscle, respectively), followed by a significant slowing of relaxation kinetics at the highest energy demands relative to WT controls. This is consistent with a depressed capacity to sequester calcium in the presence of high ADP. However, the overall pattern of fatigue in AK1 Ϫ/Ϫ mice was similar to WT control muscle. Our findings directly demonstrate the importance of AMP formation and subsequent deamination in limiting ADP accumulation. Whole muscle contractile performance was, however, remarkably tolerant of ADP accumulation markedly in excess of what normally occurs in skeletal muscle. AMP deaminase; tetanic contraction; muscle relaxation; calcium handling; cross-bridge cycling SKELETAL MUSCLE can maintain favorable energetic conditions in the face of great energetic demands. For example, the ATP consumption rate needed to support a tetanic contraction (ϳ10 mol/g per second) is ϳ200-fold above the resting rate in rat fast twitch fibers (28, 42). The metabolic challenge this represents is highlighted by the fact that the ATP content of mammalian skeletal muscle is only 6 -7 mol/g. Therefore, without compensation, the entire ATP pool would be completely depleted in Ͻ1 s at this rate. Obviously, this does not occur due to the ATP synthetic processes of oxidative phosphorylation, glycolysis, the creatine kinase (CK) reaction, and the adenylate kinase (AK) reaction. Moreover, the free energy available from ATP hydrolysis (⌬G ATP ) is a function of the ATP content relative to the products of ATP hydrolysis, namely ADP and inorganic phosphate (P i )where ⌬G°A TP is the conventional expression for the free engery of ATP at standard conditions, R is the ideal gas constant at 0.0083143 kJ/mol⅐K, and T is the temperature in Kelvin. Furthermore, the accumulation of ADP and P i direct physiological consequences independent of an impaired ⌬G ATP . Thus, the metabolic challenge when ATP turnover is high, is to preserve ATP content and limit inordinate accumulation of ADP and P i .When the rate of ATP hydrolysis is out of balance with the rate of ATP synthesis, the need to limit the accumulation of ADP and P i is the greatest. The rea...

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Section: Discussionmentioning

confidence: 99%

Section: Contractile Function the Initial Peak Tetanic Tension Was Nmentioning

confidence: 99%

Skeletal muscle contractile performance and ADP accumulation in adenylate kinase-deficient mice

Hancock¹,

Janssen²,

Terjung³

2005

American Journal of Physiology-Cell Physiology

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“…Absence of MAD occurs in approximately 2% of muscle biopsy submitted to pathologic examination for suspected neuromuscular disease 6 . MAD deficiency have been described in muscle biopsy of patients with polyneuropathy, infantile spinal muscular atrophy, congenita myopathy with type-2 fiber atrophy, facioscapulohumeral myopathy, polymyositis, dermatomyositis, myotonic dystrophy, limb-girdle muscular dystrophy, dystrophinopathies, systemic sclerosis, McArdle's disease, phosphofructokinase deficiency, and hyperornithinaemia with gyrate atrophy of the retina 3,[7][8][9] . MAD deficiency associated with other neuromuscular disorders was previously thought to be the result of a limitation in MAD transcript availability, secondary to the pathological abnormalities in a variety of neuromuscular or rheumatological disorders.…”

Section: Discussionmentioning

confidence: 99%

“…Early reports suggested that patients with MAD deficiency had a syndrome of myalgia, and exercise intolerance 2 . However, deficiency of the MAD has been described in many conditions, including myopathies, neuropathies, and motor neuron disease 3 . We report a patient with clinical diagnosis of myotonia congenita and absent myoadenylate deaminase reaction on the muscle biopsy.…”

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confidence: 99%

Myotonia congenita and myoadenylate deaminase deficiency: case report

Scola

Iwamoto

Camargo

et al. 2003

Arq. Neuro-Psiquiatr.

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-Approximately 1-2% of the population has a deficiency of the enzyme myoadenylate deaminase. Early reports suggested that patients with myoadenylate deaminase deficiency had various forms of myalgia, and exercise intolerance. However, a deficiency of the enzyme has been described in many conditions, including myopathies, neuropathies, and motor neuron disease. We report a patient with clinical diagnosis of myotonia congenita and absent myoadenylate deaminase reaction on the muscle biopsy. This is the first description of myoadenilate deaminase deficiency with myotonia congenita. Myoadenylate deaminase deficiency is the most common enzymatic deficit of muscle, and the association with other neuromuscular diseases is coincidental.KEY WORDS: myotonia congenita, myoadenilate deaminase, muscle biopsy.Miotonia congênita e deficiência de mioadenilato deaminase: relato de caso Miotonia congênita e deficiência de mioadenilato deaminase: relato de caso Miotonia congênita e deficiência de mioadenilato deaminase: relato de caso Miotonia congênita e deficiência de mioadenilato deaminase: relato de caso Miotonia congênita e deficiência de mioadenilato deaminase: relato de caso RESUMO -Aproximadamente 1-2% da população apresenta deficiência de mioadenilato deaminase (MAD). Estudos iniciais sugeriam que pacientes com deficiência de MAD apresentavam várias formas de mialgias e intolerância ao exercício. Contudo, a deficiência de MAD já foi descrita em várias situações, incluindo miopatias, neuropatias e doenças do neurônio motor. Relatamos um paciente com o diagnóstico clínico de miotonia congênita e deficiência de MAD na biópsia muscular. Essa é a primeira descrição de deficiência de MAD associada a miotonia congênita. A deficiência de MAD é o déficit enzimático mais comum nos músculos esqueléticos e sua associação com diversas doenças neuromusculares é apenas coincidência. PALAVRAS-CHAVE: miotonia congênita, mioadenilato deaminase, biópsia muscular.

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“…Screening studies with large numbers of muscle biopsies in Europe and America revealed a high prevalence of MAD of about 2-3% in all samples [33][34][35][36][37][38][39][40].…”

Section: Mad Deficiencymentioning

confidence: 99%

Molecular biology of AMP deaminase deficiency

Gross¹

1994

Pharm World Sci

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In man, there are at least four isoforms of adenosine monophosphate deaminase (AMPD): myoadenylate deaminase in skeletal muscle, the L isoform in liver, and the E1 and E2 isoforms in erythrocytes. Myoadenylate deaminase is encoded by the AMPD1 gene located on chromosome 1 p13-p21, the L isoform by the AMPD2 gene, and both isoforms in erythrocytes by the AMPD3 gene. Myoadenylate deaminase deficiency is found in 2-3% of all muscle biopsies. The inborn type of myoadenylate deaminase deficiency is caused by a single mutant allele harbouring two mutations: C34-->T (Gln-->Stop) and C143-->T (Pro-48-->Leu). Population studies revealed a frequency of the mutant allele of 0.12 in Caucasian Americans and Germans. The C34-->T mutation is located in exon 2, which is alternatively spliced in part of the AMPD1 transcript in human muscle. Since the second mutation does not affect enzyme function, alternatively spliced mRNA encodes a catalytically active enzyme. Only one patient with a disorder linked to liver AMPD has been described so far. In this patient the decreased inhibition of this enzyme by GTP resulted in uric acid overproduction and gout. A complete lack of erythroyte AMPD activity is found in asymptomatic subjects. The molecular basis of both disorders is not yet known.

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Myoadenylate deaminase deficiency: absence of correlation with exercise intolerance in 452 muscle biopsies

Cited by 31 publications

References 23 publications

Skeletal muscle contractile performance and ADP accumulation in adenylate kinase-deficient mice

Skeletal muscle contractile performance and ADP accumulation in adenylate kinase-deficient mice

Myotonia congenita and myoadenylate deaminase deficiency: case report

Molecular biology of AMP deaminase deficiency

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