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Effect of isolated AMP deaminase deficiency on skeletal muscle function ☆

View Article: PubMed Central - PubMed

ABSTRACT

Mutation of the AMP deaminase 1 (AMPD1) gene, the predominate AMPD gene expressed in skeletal muscle, is one of the most common inherited defects in the Caucasian population; 2–3% of individuals in this ethnic group are homozygous for defects in the AMPD1 gene. Several studies of human subjects have reported variable results with some studies suggesting this gene defect may cause symptoms of a metabolic myopathy and/or easy fatigability while others indicate individuals with this inherited defect are completely asymptomatic. Because of confounding problems in assessing muscle symptoms and performance in human subjects with different genetic backgrounds and different environmental experiences such as prior exercise conditioning and diet, a strain of inbred mice with selective disruption of the AMPD1 was developed to study the consequences of muscle AMPD deficiency in isolation. Studies reported here demonstrate that these animals are a good metabolic phenocopy of human AMPD1 deficiency but they exhibit no abnormalities in muscle performance in three different exercise protocols.

No MeSH data available.


AMPD activity in skeletal muscles. A: AMPD activity in gastrocnemius (Gastro), EDL, and soleus muscle tissues. Values are shown as the mean ± SE (n = 3 for wild type, n = 5 for AMPD1 heterozygote, n = 5 for AMPD1 ). *P < 0.05. (Wt: wild type, A1(+/−): AMPD1 heterozygote, A1(−/−): AMPD1 ), B: AMPD histoenzymatic stain in gastrocnemius (Gastro), EDL, and soleus muscle tissues. (Wt: wild type, A1(+/−): AMPD1 heterozygote, A1(−/−): AMPD1 ).
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f0010: AMPD activity in skeletal muscles. A: AMPD activity in gastrocnemius (Gastro), EDL, and soleus muscle tissues. Values are shown as the mean ± SE (n = 3 for wild type, n = 5 for AMPD1 heterozygote, n = 5 for AMPD1 ). *P < 0.05. (Wt: wild type, A1(+/−): AMPD1 heterozygote, A1(−/−): AMPD1 ), B: AMPD histoenzymatic stain in gastrocnemius (Gastro), EDL, and soleus muscle tissues. (Wt: wild type, A1(+/−): AMPD1 heterozygote, A1(−/−): AMPD1 ).

Mentions: AMPD1 knockout mice were generated using a standard gene targeting method (Supplemental Fig. S1A). Disruption of the AMPD1 gene was confirmed by PCR and Southern blotting (Supplemental Fig. S1B). Northern and western blots confirmed that the AMPD1 knockout homozygote [A1(−/−)] mice did not show any expression of AMPD1 RNA or protein (Figs. 1A and B). Furthermore, AMPD activity was decreased in all muscle types of AMPD1 knockout heterozygote [A1(+/−)] mice (Fig. 2A), and almost undetectable in the gastrocnemius and extensor digitorum longus (EDL) of A1(−/−) mice. In the soleus muscle of A1(−/−) mice, approximately 10% of AMPD activity remained when compared to the wild type, due to the expression of the AMPD3 gene in this muscle type [7]. AMPD1 activity as assessed by histochemical staining (Fig. 2C), a common test used in analysis of human muscle biopsies, also showed reduction or loss of AMPD enzyme activity in muscle samples from the A1(+/−) and A1(−/−) animals, respectively.


Effect of isolated AMP deaminase deficiency on skeletal muscle function ☆
AMPD activity in skeletal muscles. A: AMPD activity in gastrocnemius (Gastro), EDL, and soleus muscle tissues. Values are shown as the mean ± SE (n = 3 for wild type, n = 5 for AMPD1 heterozygote, n = 5 for AMPD1 ). *P < 0.05. (Wt: wild type, A1(+/−): AMPD1 heterozygote, A1(−/−): AMPD1 ), B: AMPD histoenzymatic stain in gastrocnemius (Gastro), EDL, and soleus muscle tissues. (Wt: wild type, A1(+/−): AMPD1 heterozygote, A1(−/−): AMPD1 ).
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5121310&req=5

f0010: AMPD activity in skeletal muscles. A: AMPD activity in gastrocnemius (Gastro), EDL, and soleus muscle tissues. Values are shown as the mean ± SE (n = 3 for wild type, n = 5 for AMPD1 heterozygote, n = 5 for AMPD1 ). *P < 0.05. (Wt: wild type, A1(+/−): AMPD1 heterozygote, A1(−/−): AMPD1 ), B: AMPD histoenzymatic stain in gastrocnemius (Gastro), EDL, and soleus muscle tissues. (Wt: wild type, A1(+/−): AMPD1 heterozygote, A1(−/−): AMPD1 ).
Mentions: AMPD1 knockout mice were generated using a standard gene targeting method (Supplemental Fig. S1A). Disruption of the AMPD1 gene was confirmed by PCR and Southern blotting (Supplemental Fig. S1B). Northern and western blots confirmed that the AMPD1 knockout homozygote [A1(−/−)] mice did not show any expression of AMPD1 RNA or protein (Figs. 1A and B). Furthermore, AMPD activity was decreased in all muscle types of AMPD1 knockout heterozygote [A1(+/−)] mice (Fig. 2A), and almost undetectable in the gastrocnemius and extensor digitorum longus (EDL) of A1(−/−) mice. In the soleus muscle of A1(−/−) mice, approximately 10% of AMPD activity remained when compared to the wild type, due to the expression of the AMPD3 gene in this muscle type [7]. AMPD1 activity as assessed by histochemical staining (Fig. 2C), a common test used in analysis of human muscle biopsies, also showed reduction or loss of AMPD enzyme activity in muscle samples from the A1(+/−) and A1(−/−) animals, respectively.

View Article: PubMed Central - PubMed

ABSTRACT

Mutation of the AMP deaminase 1 (AMPD1) gene, the predominate AMPD gene expressed in skeletal muscle, is one of the most common inherited defects in the Caucasian population; 2&ndash;3% of individuals in this ethnic group are homozygous for defects in the AMPD1 gene. Several studies of human subjects have reported variable results with some studies suggesting this gene defect may cause symptoms of a metabolic myopathy and/or easy fatigability while others indicate individuals with this inherited defect are completely asymptomatic. Because of confounding problems in assessing muscle symptoms and performance in human subjects with different genetic backgrounds and different environmental experiences such as prior exercise conditioning and diet, a strain of inbred mice with selective disruption of the AMPD1 was developed to study the consequences of muscle AMPD deficiency in isolation. Studies reported here demonstrate that these animals are a good metabolic phenocopy of human AMPD1 deficiency but they exhibit no abnormalities in muscle performance in three different exercise protocols.

No MeSH data available.