Abstract
Purpose: 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.
Highlights
Carnitine, 4-trimethylamino-3-hydroxy butyric acid, is present in all mammalian tissues and is ingested by the diet or produced by endogenous biosynthesis from trimethyllysine (Bremer, 1983; Hoppel and Davis, 1986; Vaz and Wanders, 2002)
Treatment with THP was associated with a marked atrophy of the oxidative soleus muscle as well as with impaired activity of complex II and IV of the electron transport chain, a decrease in the cellular glutathione pool, a decrease in the mRNA expression of regulators of mitochondrial biogenesis, and reduced mitochondrial DNA content compared to control rats
We have shown repeatedly that treatment with THP for 21 days is associated with a 70–80% decrease in the skeletal muscle carnitine content (Spaniol et al, 2001; Zaugg et al, 2003; Roberts et al, 2015)
Summary
4-trimethylamino-3-hydroxy butyric acid, is present in all mammalian tissues and is ingested by the diet or produced by endogenous biosynthesis from trimethyllysine (Bremer, 1983; Hoppel and Davis, 1986; Vaz and Wanders, 2002). The major carnitine body pool, accounting for >95% of the total body stores, is located in skeletal muscle (Hoppel and Davis, 1986; Krähenbühl et al, 2000; Spaniol et al, 2001). Carnitine is an obligatory intermediate for the transport of long chain fatty acids across this inner mitochondrial membrane and plays an essential role in cellular energy metabolism due to acylation of its β-hydroxyl group (Fritz and Mc, 1959; Bremer, 1983). Carnitine is important for buffering the free pool of coenzyme A (CoASH). Carnitine shifts the acyl-CoA to CoA-SH ratio in the direction of CoASH and is thereby involved in trapping acyl residues from peroxisomes and mitochondria (Brass and Hoppel, 1980; Friolet et al, 1994)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
