Contractile function and energy metabolism of skeletal muscle in rats with secondary carnitine deficiency

Abstract

-The consequences of carnitine depletion upon metabolic and contractile characteristics of skeletal muscle remain largely unexplored. Therefore, we investigated the effect of N-trimethyl-hydrazine-3-propionate (THP) administration, a carnitine analog inhibiting carnitine biosynthesis and renal reabsorption of carnitine, on skeletal muscle function and energy metabolism. Male Sprague-Dawley rats were fed a standard rat chow in the absence (CON; n ϭ 8) or presence of THP (n ϭ 8) for 3 wk. Following treatment, rats were fasted for 24 h prior to excision of their soleus and EDL muscles for biochemical characterization at rest and following 5 min of contraction in vitro. THP treatment reduced the carnitine pool by ϳ80% in both soleus and EDL muscles compared with CON. Carnitine depletion was associated with a 30% decrease soleus muscle weight, whereas contractile function (expressed per gram of muscle), free coenzyme A, and water content remained unaltered from CON. Muscle fiber distribution and fiber area remained unaffected, whereas markers of apoptosis were increased in soleus muscle of THP-treated rats. In EDL muscle, carnitine depletion was associated with reduced free coenzyme A availability (Ϫ25%, P Ͻ 0.05), impaired peak tension development (Ϫ44%, P Ͻ 0.05), and increased glycogen hydrolysis (52%, P Ͻ 0.05) during muscle contraction, whereas PDC activation, muscle weight, and water content remained unaltered from CON. In conclusion, myopathy associated with carnitine deficiency can have different causes. Although muscle atrophy, most likely due to increased apoptosis, is predominant in muscle composed predominantly of type I fibers (soleus), disturbance of energy metabolism appears to be the major cause in muscle composed of type II fibers (EDL).N-trimethyl-hydrazine-3-propionate; secondary carnitine deficiency; carbohydrate metabolism; muscle atrophy; apoptosis CARNITINE IS A NATURALLY OCCURRING COMPOUND that is found in all mammalian tissues. L-Carnitine, the biologically effective isomer, plays a key role within several cellular energy producing pathways (9). For instance, carnitine is essential for the transport of long-chain fatty acids across the inner mitochondrial membrane toward their oxidative fate inside the mitochondrial matrix (15), is important for the removal of potentially toxic acyl-CoAs from the mitochondria by forming acylcarnitines (3, 6), and serves as a temporal acetyl group buffer in the oxidation of carbohydrates during periods of augmented pathway flux (14, 31).Fundamental to our understanding of the role of carnitine within the body is the ability to manipulate the size of the tissue carnitine pool and to investigate the consequences of such upon cellular, tissue, and whole body functions at rest and in response to external stresses such as muscular contraction. Although recent studies have shown that the skeletal muscle carnitine content can be increased in the presence of high circulating insulin concentrations by ϳ20% in humans (39,40,46), it appears to be more difficult to increa...

Muscle carnitine availability plays a central role in regulating fuel metabolism in the rodent

“…Moreover, administration of meldonium to rodents in vivo increased urinary free carnitine excretion by 30-fold (Kuwajima et al 1999;Spaniol et al 2001). In the present study, 10 days of meldonium treatment resulted in substantial differences in muscle total carnitine content compared to the control in two rodent species, which is consistent with the observations reported elsewhere (Spaniol et al 2001;Roberts et al 2015). Furthermore, we demonstrated that this effect was distributed across all muscle carnitine esters, and in the heart and muscles of widely different metabolic phenotypes (Tables 1 and 2).…”

“…; Roberts et al . ). Furthermore, we demonstrated that this effect was distributed across all muscle carnitine esters, and in the heart and muscles of widely different metabolic phenotypes (Tables and ).…”

“…Although meldonium-mediated carnitine depletion has been reported in mixed-fibred rodent gastrocnemius (Tsoko et al 1995) and quadriceps femoris (Spaniol et al 2001) muscles, little is known regarding its relative impact on muscles of widely different metabolic and physiological characteristics, particularly from the same animal. Roberts et al (2015) reported that, compared to the control, meldonium-mediated carnitine depletion was associated with reduced tension development and increased glycogen hydrolysis over 5 min of fatiguing contraction in muscle composed of predominantly Type II fibres [extensor digitorum longus (EDL)]. This contrasted with the response seen in the slow contracting soleus muscle where contractile function and energy metabolism during contraction were apparently unaffected compared to the control.…”

“…Roberts et al . () reported that, compared to the control, meldonium‐mediated carnitine depletion was associated with reduced tension development and increased glycogen hydrolysis over 5 min of fatiguing contraction in muscle composed of predominantly Type II fibres [extensor digitorum longus (EDL)]. This contrasted with the response seen in the slow contracting soleus muscle where contractile function and energy metabolism during contraction were apparently unaffected compared to the control.…”

Carnitine deficiency is associated with decreased exercise activity in hemodialysis patients

“…We, along with others, have reported that serum carnitine levels were significantly decreased in HD patients because 60-80% of serum carnitine is eliminated from the blood via HD [6,7]. Since carnitine depletion reportedly has been associated with decreased soleus muscle weight in a rat model of carnitine deficiency [8], carnitine deficiency may be a causative factor for HD-related exercise inactivity in ESRD patients.…”