Abstract
BackgroundRecently, it has been shown that carnitine down-regulates genes involved in the ubiquitin-proteasome system (UPS) in muscle of pigs and rats. The mechanisms underlying this observation are yet unknown. Based on the previous finding that carnitine increases plasma IGF-1 concentration, we investigated the hypothesis that carnitine down-regulates genes of the UPS by modulation of the of the IGF-1/PI3K/Akt signalling pathway which is an important regulator of UPS activity in muscle.MethodsMale Sprague–Dawley rats, aged four weeks, were fed either a control diet with a low native carnitine concentration or the same diet supplemented with carnitine (1250 mg/kg diet) for four weeks. Components of the UPS and IGF-1/PI3K/Akt signalling pathway in skeletal muscle were examined.ResultsRats fed the diet supplemented with carnitine had lower mRNA and protein levels of MuRF1, the most important E3 ubiquitin ligase in muscle, decreased concentrations of ubiquitin-protein conjugates in skeletal muscle and higher IGF-1 concentration in plasma than control rats (P < 0.05). Moreover, in skeletal muscle of rats fed the diet supplemented with carnitine there was an activation of the PI3K/Akt signalling pathway, as indicated by increased protein levels of phosphorylated (activated) Akt1 (P < 0.05).ConclusionThe present study shows that supplementation of carnitine markedly decreases the expression of MuRF1 and concentrations of ubiquitinated proteins in skeletal muscle of rats, indicating a diminished degradation of myofibrillar proteins by the UPS. The study moreover shows that supplementation of carnitine leads to an activation of the IGF-1/PI3K/Akt signalling pathway which in turn might contribute to the observed down-regulation of MuRF1 and muscle protein ubiquitination.
Highlights
It has been shown that carnitine down-regulates genes involved in the ubiquitin-proteasome system (UPS) in muscle of pigs and rats
Growth performance and skeletal muscle weights Food intake, final body weights after four weeks, feed conversion ratio (g feed/g body weight gain) and weights of M. quadriceps femoris, M. extensor digitorum longus, M. gastrocnemius and M. soleus were not different between both groups of rats (P > 0.05; Table 2)
Concentrations of proteins and triglycerides in muscles In order to investigate whether carnitine supplementation could have an influence on the composition of muscles, concentrations of protein and triglycerides in M. quadriceps femoris, M. extensor digitorum longus and M. gastrocnemius were determined
Summary
It has been shown that carnitine down-regulates genes involved in the ubiquitin-proteasome system (UPS) in muscle of pigs and rats. The mechanisms underlying this observation are yet unknown. It was shown that genetic deletion of MuRF1 and atrogin-1 results in significantly increased sparing of muscle mass loss induced by muscle denervation. This clearly demonstrates the important role of these atrophy-regulated genes as key factors of myofibrillar protein breakdown by the ubiquitin-dependent proteolysis [7]
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