title: Impaired Exercise Performance and Skeletal Muscle Mitochondrial Function in Rats with Secondary Carnitine Deficiency.
abstract: OBJECTIVE
  The effects of carnitine depletion upon exercise performance and skeletal muscle mitochondrial function remain largely unexplored. We therefore investigated the effect of N-trimethyl-hydrazine-3-propionate (THP), a carnitine analog inhibiting carnitine biosynthesis and renal carnitine reabsorption, on physical performance and skeletal muscle mitochondrial function in rats.
  
  
  METHODS
  Male Sprague Dawley rats were treated daily with water (control rats; n = 12) or with 20 mg/100 g body weight THP (n = 12) via oral gavage for 3 weeks. Following treatment, half of the animals of each group performed an exercise test until exhaustion.
  
  
  RESULTS
  Distance covered and exercise performance were lower in THP-treated compared to control rats. In the oxidative soleus muscle, carnitine depletion caused atrophy (-24%) and impaired function of complex II and IV of the mitochondrial electron transport chain. The free radical leak (ROS production relative to oxygen consumption) was increased and the cellular glutathione pool decreased. Moreover, mRNA expression of markers of mitochondrial biogenesis and mitochondrial DNA were decreased in THP-treated compared to control rats. In comparison, in the glycolytic gastrocnemius muscle, carnitine depletion was associated with impaired function of complex IV and increased free radical leak, whilst muscle weight and cellular glutathione pool were maintained. Markers of mitochondrial proliferation and mitochondrial DNA were unaffected.
  
  
  CONCLUSIONS
  Carnitine deficiency is associated with impaired exercise capacity in rats treated with THP. THP-induced carnitine deficiency is associated with impaired function of the electron transport chain in oxidative and glycolytic muscle as well as with atrophy and decreased mitochondrial DNA in oxidative muscle.
authors: Department of Clinical Pharmacology and Toxicology, University Hospital BaselBasel, Switzerland; Department of Biomedicine, University of BaselBasel, Switzerland; Swiss Centre of Applied Human ToxicologyBasel, Switzerland.
authors: Jamal
authors: J
authors: Bouitbir
authors: Department of Clinical Pharmacology and Toxicology, University Hospital BaselBasel, Switzerland; Department of Biomedicine, University of BaselBasel, Switzerland.
authors: Patrizia
authors: P
authors: Haegler
authors: Department of Clinical Pharmacology and Toxicology, University Hospital BaselBasel, Switzerland; Department of Biomedicine, University of BaselBasel, Switzerland; Fédération de Médecine Translationelle, Faculté de Médecine, Institut de Physiologie, Université de StrasbourgStrasbourg, France.
authors: François
authors: F
authors: Singh
authors: Department of Clinical Pharmacology and Toxicology, University Hospital BaselBasel, Switzerland; Department of Biomedicine, University of BaselBasel, Switzerland.
authors: Lorenz
authors: L
authors: Joerin
authors: Department of Clinical Pharmacology and Toxicology, University Hospital BaselBasel, Switzerland; Department of Biomedicine, University of BaselBasel, Switzerland.
authors: Andrea
authors: A
authors: Felser
authors: Department of Clinical Pharmacology and Toxicology, University Hospital BaselBasel, Switzerland; Department of Biomedicine, University of BaselBasel, Switzerland.
authors: Urs
authors: U
authors: Duthaler
authors: Department of Clinical Pharmacology and Toxicology, University Hospital BaselBasel, Switzerland; Department of Biomedicine, University of BaselBasel, Switzerland; Swiss Centre of Applied Human ToxicologyBasel, Switzerland.
authors: Stephan
authors: S
authors: Krähenbühl
keywords: N-trimethyl-hydrazine-3-propionate; carnitine deficiency; exhaustive exercise; mitochondria; reactive oxygen species; skeletal muscle