title: Hyperammonemia results in reduced muscle function independent of muscle mass.
abstract: The mechanism of the nearly universal decreased muscle strength in cirrhosis is not known. We evaluated whether hyperammonemia in cirrhosis causes contractile dysfunction independent of reduced skeletal muscle mass. Maximum grip strength and muscle fatigue response were determined in cirrhotic patients and controls. Blood and muscle ammonia concentrations and grip strength normalized to lean body mass were measured in the portacaval anastomosis (PCA) and sham-operated pair-fed control rats (n = 5 each). Ex vivo contractile studies in the soleus muscle from a separate group of Sprague-Dawley rats (n = 7) were performed. Skeletal muscle force of contraction, rate of force development, and rate of relaxation were measured. Muscles were also subjected to a series of pulse trains at a range of stimulation frequencies from 20 to 110 Hz. Cirrhotic patients had lower maximum grip strength and greater muscle fatigue than control subjects. PCA rats had a 52.7 ± 13% lower normalized grip strength compared with control rats, and grip strength correlated with the blood and muscle ammonia concentrations (r(2) = 0.82). In ex vivo muscle preparations following a single pulse, the maximal force, rate of force development, and rate of relaxation were 12.1 ± 3.5 g vs. 6.2 ± 2.1 g; 398.2 ± 100.4 g/s vs. 163.8 ± 97.4 g/s; -101.2 ± 22.2 g/s vs. -33.6 ± 22.3 g/s in ammonia-treated compared with control muscle preparation, respectively (P < 0.001 for all comparisons). Tetanic force, rate of force development, and rate of relaxation were depressed across a range of stimulation from 20 to 110 Hz. These data provide the first direct evidence that hyperammonemia impairs skeletal muscle strength and increased muscle fatigue and identifies a potential therapeutic target in cirrhotic patients.
authors.affiliation: Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio; Department of Exercise Science, Kent State University Kent, Ohio;
authors.forename: John
authors.initials: J
authors.lastname: McDaniel
authors.affiliation: Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio;
authors.forename: Gangarao
authors.initials: G
authors.lastname: Davuluri
authors.affiliation: Department of Medicine, Cleveland Clinic, Cleveland, Ohio;
authors.forename: Elizabeth Ann
authors.initials: EA
authors.lastname: Hill
authors.affiliation: Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio;
authors.forename: Michelle
authors.initials: M
authors.lastname: Moyer
authors.affiliation: Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio; Department of Medicine, Cleveland Clinic, Cleveland, Ohio;
authors.forename: Ashok
authors.initials: A
authors.lastname: Runkana
authors.affiliation: Department of Pathology, Cleveland Clinic, Cleveland, Ohio;
authors.forename: Richard
authors.initials: R
authors.lastname: Prayson
authors.affiliation: Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio; Case Western Reserve University Cleveland, Ohio.
authors.forename: Erik
authors.initials: E
authors.lastname: van Lunteren
authors.affiliation: Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio; Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio; and dasaras@ccf.org.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Dasarathy
mesh_terms: D000368:Aged; D000641:Ammonia / Q000097:blood; D000818:Animals; D004558:Electric Stimulation; D005260:Female; D018737:Hand Strength; D006801:Humans; D022124:Hyperammonemia / Q000150:complications* / Q000473:pathology*; D008103:Liver Cirrhosis / Q000150:complications / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction; D018763:Muscle Fatigue; D009126:Muscle Relaxation; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000473:pathology*; D018995:Myosin Heavy Chains / Q000378:metabolism; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000641:Ammonia; D018995:Myosin Heavy Chains
keywords: cirrhosis; force; hyperammonemia; skeletal muscle