title: Skeletal muscle protein loss due to D-penicillamine results from reduced protein synthesis.
abstract: Reports in the literature indicate that the trifunctional amino acid D-penicillamine (D-P) induces a variety of muscle abnormalities, although the mechanisms are unknown. We hypothesised that defects may also arise due to the effects of D-P on rates of protein synthesis, possibly via changes in muscle metal composition. Male Wistar rats were injected with D-P at doses of 50 and 500 mg/kg body weight, i.p. Rats designated as controls were injected with 0.15 mol/l NaCl. After 24 h, there were reductions in muscle protein contents, protein synthetic capacities (RNA:protein ratio), fractional rates of protein synthesis, synthesis rates per unit RNA and synthesis rates per unit DNA in skeletal muscles of D-P treated rats. There were no statistically significant differences between the responses of the muscles containing a predominance of either Type I (represented by the soleus) or Type II (represented by the plantaris) fibres. In general, intracellular amino acids were not significantly affected by D-P treatment. Changes in muscle metals included significant reductions in copper, iron and manganese, without alterations in zinc or magnesium. In liver D-P reduced copper and iron though zinc, manganese and magnesium were unaffected. These effects of D-P on muscle may have been direct, as plasma indices of liver (activities of alkaline phosphatase and alanine aminotransferase) and kidney (urea, creatinine and electrolytes) damage were not significantly altered by D-P treatment. Plasma levels of corticosterone, insulin and free T3 were also not significantly affected by D-P treatment. Muscle protein carbonyl concentrations, an index of free radical activity, were similarly unaffected. This is the first report of reduced rates of muscle protein synthesis in D-P treatment. Our data suggests that the reduced rates of muscle protein synthesis may contribute to, or reflect, the muscle abnormalities observed in patients undergoing D-P treatment.
authors.affiliation: Molecular and Cellular Protein Biochemistry Laboratory, Department of Nutrition and Dietetics, King's College London 150 Stamford Street, SE1 9NN, London, UK. victor.preedy@kcl.ac.uk
authors.forename: V R
authors.initials: VR
authors.lastname: Preedy
authors.forename: W S
authors.initials: WS
authors.lastname: Wassif
authors.forename: D
authors.initials: D
authors.lastname: Baldwin
authors.forename: J
authors.initials: J
authors.lastname: Jones
authors.forename: G
authors.initials: G
authors.lastname: Falkous
authors.forename: J S
authors.initials: JS
authors.lastname: Marway
authors.forename: D
authors.initials: D
authors.lastname: Mantle
authors.forename: D L
authors.initials: DL
authors.lastname: Scott
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000009:adverse effects*; D003300:Copper / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007501:Iron / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008345:Manganese / Q000378:metabolism; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000502:physiology; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects / Q000502:physiology; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009929:Organ Size; D010396:Penicillamine / Q000008:administration & dosage / Q000009:adverse effects*; D051381:Rats; D017208:Rats, Wistar; D013054:Spectrophotometry, Atomic; D013997:Time Factors; D015032:Zinc / Q000378:metabolism
chemical_list: D018501:Antirheumatic Agents; D009124:Muscle Proteins; D008345:Manganese; D003300:Copper; D007501:Iron; D010396:Penicillamine; D015032:Zinc