Cyclic nucleotide phosphodiesterase isozymes expressed in mouse skeletal muscle

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Abstract:



To understand changes in cyclic nucleotide metabolism in muscle disease states, the expression of phosphodiesterase (PDE) isozymes in normal mouse leg muscle was examined. Four subcellular fractions were generated by differential centrifugation at 10 000 × g and 100 000 × g. cAMP PDE activity was found predominately in the soluble fractions, while cGMP PDE activity was more evenly distributed amongst soluble and particulate fractions. Pharmacological inhibitors demonstrate that PDE4 represents the major cAMP hydrolyzing activity and PDE2 represents the major cGMP hydrolyzing activity in mouse leg muscle. PDE1 is expressed at low levels, while PDE3 and PDE5 are intermediate. Between 20 and 40% of total PDE activity remained in the presence of inhibitors for PDE1–PDE5, indicating that other PDE families contribute to the total PDE pool. Reverse-transcription PCR with family-specific primers showed expression of mRNA for PDE7–PDE9, supporting this conclusion. Total PDE activity was found to be elevated in tissue extracts from a mouse model of Duchenne's muscular dystrophy.Key words: cyclic nucleotide, phosphodiesterase, skeletal muscle, pharmacological inhibitors, muscular dystrophy.

Pour comprendre les modifications du métabolisme des nucléotides cycliques dans les maladies musculaires, on a examiné l'expression des isoenzymes de la phosphodiestérase (PDE) dans le muscle jambier normal de souris. On a produit quatre fractions subcellulaires par centrifugation différentielle à 10 000 × g et 100 000 × g. L'activité PDE de l'AMPc a été prédominante dans les fractions solubles alors que celle du GMPc a été répartie de manière plus uniforme entre les fractions solubles et particulaires. Les inhibiteurs pharmacologiques démontrent que la PDE4 représente l'activité d'hydrolyse majeure de l'AMPc et que la PDE2 représente celle du GMPc dans le muscle jambier de souris. La PDE1 est faiblement exprimée alors que la PDE3 et la PDE5 le sont moyennement. Entre 20–40  % de l'activité PDE totale subsistent en présence d'inhibiteurs de la PDE1–PDE5, ce qui indique que d'autres familles de PDE participent au pool total de PDE. La RT–PCR avec des amorces spécifiques des familles a montré l'expression d'un ARNm pour la PDE7–PDE9, confortant cette conclusion. L'activité PDE totale s'est révélée élevée dans les extraits tissulaires d'un modèle murin de dystrophie musculaire de Duchenne.Mots clés : nucléotide cyclique, phosphodiestérase, muscle squelettique, inhibiteurs pharmacologiques, dystrophie musculaire.[Traduit par la Rédaction]
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