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Differential mechanisms of ammonia transport in the liver and skeletal muscle (893.30)
Author(s) -
Worrell Roger,
Dasarathy Srinivasan
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.893.30
Subject(s) - skeletal muscle , hyperammonemia , myogenesis , endocrinology , myocyte , chemistry , medicine , c2c12 , hepatic encephalopathy , ammonium chloride , biochemistry , biology , cirrhosis , organic chemistry
Hyperammonemia is a consistent abnormality in cirrhosis due to impaired ureagenesis and contributes to both encephalopathy and sarcopenia, or loss of skeletal muscle mass. Recent data suggests that the skeletal muscle functions as a metabolic partner for the liver in ammonia disposal. We determined the mechanism of ammonia transport in the skeletal muscle using biopsy samples from cirrhotic patients and C2C12 murine myotubes exposed to 10mM ammonium acetate. Intracellular pH measurement was done using pH‐sensitive dye, 2',7'‐biscarboxyl‐ethyl‐5(6)‐carboxyfluorescein (BCECF). In response to ammonium acetate as well as ammonium chloride, there was a rapid ammonia influx into the myotubes. Quantifying the Rh group of ammonia transporters showed that human skeletal muscle had very low level mRNA expression for RhB. C2C12 myotubes expressed RhBG and RhCG mRNA. Interestingly, the expression of RhBG and RhCG mRNA in C2C12 myotubes was significantly lower during hyperammonemia than in control cells. Human liver tissue robustly expressed only RhBG mRNA with no detectable RhCG mRNA. Alternative ammonia transporters in the skeletal muscle including NKCC1 and K + /H + ‐ATPase likely play a role. These data suggest that ammonia transport in the liver is mediated differently from that in the skeletal muscle. These data are of high clinical significance since under normal conditions, the liver is the major organ for ammonia transport while in cirrhosis, skeletal muscle uptake of ammonia is significantly increased. Understanding the regulation of ammonia transport has the potential to develop mechanistic and targeted therapies for hyperammonemia. Grant Funding Source : Supported by NIH DK 083414 to SD and NIH DK079979 to RTW