Adaptive changes in cardiac myosin heavy chain and creatine kinase isozymic profiles in rats native of altitude.

AIM: The developmental changes in the myosin heavy chain (MHC) profile, creatine kinase (CK) and lactate dehydrogenase (LDH) activities and isozyme expression occurring in heart were examined in rats born and living at altitude (La Paz, Bolivia, 3700 m, H(LP)) for 16 generations. We hypothesized that H(LP) rats respond differently to hypoxia than rats born and living at sea level, and secondarily exposed to altitude during 3 weeks (H(3W)). METHODS: The cardiac expression of MHC, CK and LDH was studied in left (LV) and right ventricle (RV) of H(LP) animals 1, 2, 3, 4 and 18 weeks after birth, and compared with control normoxic (C groups) and H(3W) animals. RESULTS: Rats secondarily exposed to hypoxia showed a lower alpha-MHC content than C or H(LP) rats in both LV and RV, 3 weeks after birth (P < 0.05), consistent with a delay in the maturation of the heart contractile phenotype. A global increase in the total CK activity was observed in the LV of H(3W) animals in comparison with C rats (P < 0.05), while no change was reported in H(LP) animals. In both ventricles, M-LDH activity was higher in H(3W) than in H(LP) and C rats (P < 0.05). The relative amount of alpha-MHC decreased by 20% in RV of 18-week-old H(LP) and H(3W) rats in comparison with C animals, consistent with the hypoxia-induced ventricular enlargement (P < 0.01). An increased activity of the foetal B-CK subunit was observed in both LV and RV of H(3W) rats in comparison with H(LP) and C animals (P < 0.05). CONCLUSION: This study demonstrates that rats native and living at altitude for several generations present some features relevant to genetic selection to altitude.

Differential effects of thyroid hormones on energy metabolism of rat slow- and fast-twitch muscles.

Thyroid hormone (TH) is an important regulator of mitochondrial content and activity. As mitochondrial content and properties differ depending on muscle-type, we compared mitochondrial regulation and biogenesis by T3 in slow-twitch oxidative (soleus) and fast-twitch mixed muscle (plantaris). Male Wistar rats were treated for 21 to 27 days with T3 (200 microg/kg/day). Oxidative capacity, regulation of mitochondrial respiration by substrates and phosphate acceptors, and transcription factors were studied. In soleus, T3 treatment increased maximal oxygen consumption (Vmax) and the activities of citrate synthase (CS) and cytochrome oxidase (COX) by 100%, 45%, and 71%, respectively (P < 0.001), whereas in plantaris only Vmax increased, by 39% (P < 0.01). ADP-independent respiration rate was increased in soleus muscle by 216% suggesting mitochondrial uncoupling. Mitochondrial substrate utilization in soleus was also influenced by T3, as were mitochondrial enzymes. Lactate dehydrogenase (LDH) activity was elevated in soleus and plantaris by 63% and 11%, respectively (P < 0.01), and soleus creatine kinase was increased by 48% (P < 0.001). T3 increased the mRNA content of the transcriptional co-activator of mitochondrial genes, PGC-1alpha, and the I and IV COX subunits in soleus. The muscle specific response to thyroid hormones could be explained by a lower content of TH receptors in plantaris than soleus. Moreover, TRalpha mRNA level decreased further after T3 treatment. These results demonstrate that TH has a major effect on mitochondrial content, regulation and coupling in slow oxidative muscle, but to a lesser extent in fast muscle, due to the high expression of TH receptors and PGC-1alpha transcription factor.

Does ACE inhibition enhance endurance performance and muscle energy metabolism in rats?

The renin-angiotensin-aldosterone system plays an important role in the hydroelectrolytic balance, blood pressure regulation, and cell growth. In some studies, the insertion (I) allele of the angiotensin-converting enzyme (ACE) gene, associated with a lower ACE activity, has been found in excess frequency in elite endurance athletes, suggesting that decreased ACE activity could be involved in endurance performance (Myerson S, Hemingway H, Budget R, Martin J, Humphries S, and Montgomery H. J Appl Physiol 87: 1313-1316, 1999). To test this hypothesis, we evaluated whether ACE inhibition could be associated with improved endurance performance and muscle oxidative capacity in rats. Eight male Wistar rats were treated for 10-12 wk with an ACE inhibitor, perindopril (2 mg.kg-1.day-1), and compared with eight control rats. Endurance time was measured on a treadmill, and oxidative capacity and regulation of mitochondrial respiration by substrates were evaluated in saponin-permeabilized fibers of slow soleus and fast gastrocnemius muscles. Endurance time did not differ between groups (57 +/- 5 min for perindopril vs. 55 +/- 6 min for control). Absolute and relative (to body weight) left ventricular weight was 20% (P < 0.01) and 12% (P < 0.01) lower, respectively, in the treated group. No difference in oxidative capacity, mitochondrial enzyme activities, or mitochondrial regulation by ADP was observed in soleus or gastrocnemius. Mitochondrial respiration with glycerol 3-phosphate was 17% higher in gastrocnemius (P < 0.03) and with octanoylcarnitine 14% greater in soleus (P < 0.01) of treated rats. These results demonstrate that ACE inhibition was not associated with improved endurance time and maximal oxidative capacity of skeletal muscles. This suggests that ACE activity has no implication in endurance capacity and only minor effects on mitochondrial function in sedentary animals.