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J Appl Physiol 100: 1765-1769, 2006. First published January 19, 2006; doi:10.1152/japplphysiol.01533.2005
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Enhanced mitochondrial sensitivity to creatine in rats bred for high aerobic capacity

B. Walsh,1 R. B. Hooks,2 J. E. Hornyak,3 L. G. Koch,3 S. L. Britton,3 and M. C. Hogan1

1Physiology Division, Department of Medicine, University of California-San Diego, La Jolla; 2Department of Kinesiology, California State University Northridge, Northridge, California; and 3Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, Michigan

Submitted 6 December 2005 ; accepted in final form 11 January 2006


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Qualitative and quantitative measures of mitochondrial function were performed in rats selectively bred 15 generations for intrinsic aerobic high running capacity (HCR; n = 8) or low running capacity (LCR; n = 8). As estimated from a speed-ramped treadmill exercise test to exhaustion (15° slope; initial velocity of 10 m/min, increased 1 m/min every 2 min), HCR rats ran 10 times further (2,375 ± 80 m) compared with LCR rats (238 ± 12 m). Fiber bundles were obtained from the soleus and chemically permeabilized. Respiration was measured 1) in the absence of ADP, 2) in the presence of a submaximally stimulating concentration of ADP (0.1 mM ADP, with and without 20 mM creatine), and 3) in the presence of a maximally stimulating concentration of ADP (2 mM). Although non-ADP-stimulated and maximally ADP-stimulated rates of respiration were 13% higher in HCR compared with LCR, the difference was not statistically significant (P > 0.05). Despite a similar rate of respiration in the presence of 0.1 mM ADP, HCR rats demonstrated a higher rate of respiration in the presence of 0.1 mM ADP + 20 mM creatine (HCR 33% higher vs. LCR, P < 0.05). Thus mitochondria from HCR rats exhibit enhanced mitochondrial sensitivity to creatine (i.e., the ability of creatine to decrease the Km for ADP). We propose that increased respiratory sensitivity to ADP in the presence of creatine can effectively increase muscle sensitivity to ADP during exercise (when creatine is increased) and may be, in part, a contributing factor for the increased running capacity in HCR rats.

ADP; skeletal muscle; oxidative phosphorylation; exercise; high-capacity runners; low-capacity runners

ALTHOUGH CARDIOPULMONARY FACTORS are crucial in determining maximal oxygen consumption (VO2 max), local oxidative capacity is another key component to aerobic exercise performance. For a given rate of submaximal steady-state work, a greater local oxidative capacity (i.e., mitochondrial density) will require a lesser degree of activation per mitochondrion to achieve a given rate of oxygen uptake (10, 17). This, in turn, elicits smaller increases in controllers of respiration (e.g., ADP and Pi) at a given submaximal rate of work. Thus increased mitochondrial density that accompanies chronic endurance training will lead to favorable adaptations such as altered substrate utilization and decreased blood lactate accumulation in exercising skeletal muscle (10).

In addition to quantitative changes in local oxidative capacity, qualitative properties of mitochondrial function are altered with exercise training. These qualitative alterations include an increased maximal ATP production rate via fatty acids compared with other substrates (38), decreased sensitivity of the mitochondrion to ADP (ADP sensitivity) (31, 36), and an enhanced ability of creatine (Cr) to further increase the rate of submaximally ADP-stimulated respiration (18). However, it remains unclear whether these qualitative changes in mitochondrial function are directly in response to exercise per se or whether they are related to an inherent capacity of muscle metabolism during exercise.

We previously reported the development of rats artificially selected for low and high intrinsic aerobic running capacity (13). With the exception of a test to evaluate aerobic treadmill running capacity, the rats remain sedentary throughout their lifetime; accordingly, differences between lines reflect genetically determined differences in intrinsic exercise capacity. After 15 generations, maximal distance run during an incremental exercise test to exhaustion was 10-fold greater in high-capacity runners (HCR) compared with low-capacity runners (LCR). Therefore, rats selectively bred for high or low innate exercise capacity offer a unique method by which to further investigate the origin of the quantitative and qualitative differences in mitochondrial function observed after exercise training.

In the present study we measured quantitative and qualitative mitochondrial function in permeabilized fiber bundles from the soleus of generation 15 LCR and HCR rats. The use of permeabilized fibers allowed mitochondria to be assessed in their natural structural environment, making measurements of ADP sensitivity and respiratory stimulation by Cr possible (27). Specifically, we tested the hypothesis that the decrease in ADP sensitivity and increase in Cr sensitivity observed after endurance training are not directly related to exercise per se but rather to the oxidative and exercise capacity of the muscle.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subject data.   The development of the LCR and HCR was described in detail previously (13). Briefly, artificial, divergent, selective breeding was used to create low and high lines for intrinsic (untrained) treadmill running capacity. The founder population was 80 male and 88 female genetically heterogeneous rats (N:NIH stock) obtained from a colony developed at the National Institutes of Health (7). Each rat in the founder population was of different parentage so that selection was not among brothers and sisters, which produced a broader initial genetic variance (8).

After six generations, maximal distance run to exhaustion was on average threefold higher in HCR than LCR. VO2 max of extreme examples of generation 7 females (7-fold difference in running capacity) was 12% higher in HCR than in LCR (9). The higher VO2 max of HCR was not due to differences in central factors but rather due to a greater ability to transport oxygen from the tissue capillaries to the cells (9) and by increased utilization of oxygen by skeletal muscle cells (11). This greater oxidative capacity paralleled greater capillary density, higher oxidative enzyme citrate synthase and beta-hydroxyacyl-CoA dehydrogenase, and no difference in resting skeletal muscle [ATP] (brackets denote concentration) (11). Data collected at generations 10 and 11 show differences in a number of key mitochondrial proteins between the LCR and HCR rats and suggest that an impairment of mitochondrial function links low intrinsic aerobic capacity to risks for cardiovascular and metabolic disease (39). For this study, female rats were obtained from a colony housed at the Medical University of Ohio and shipped to the University of California, San Diego at 16 wk of age.

Assessment of running capacity.   The protocol for estimation of exercise capacity required 2 wk and was started when the rats were 10 wk old (13). The first week consisted of placing the rats on the treadmill (model Exer-4, Columbus Instruments, Columbus, OH) for increasing duration each day, until the animals were able to run 5 min at 10 m/min on a 15° slope. During the second week, each rat underwent a daily exercise trial on 5 consecutive days at a constant slope of 15° and an initial velocity of 10 m/min. Treadmill velocity was increased by 1 m/min every 2 min until the third time a rat could no longer keep pace with the speed of the treadmill. For each of the five trials, the total distance run (in m) was used as the estimate of exercise capacity. The single best daily run of five trials for each rat was considered the trial most closely associated with the heritable component of exercise capacity.

Eight LCR and eight HCR female rats representing the extremes of generation 15 were selected for the present study. Age was not different between groups (31.1 ± 0.7 wk LCR vs. 29.8 ± 0.5 wk HCR). The LCR rats weighed significantly more than HCR rats (251 ± 12 vs. 183 ± 7 g; P < 0.05).

Tissue preparation.   Both left and right soleus muscles were removed intact immediately after death by pentobarbital sodium (60 mg/kg iv). A transverse slice from the widest point of the middle belly portion of either the left or right soleus (randomized) was excised and frozen in precooled isopentane (–140°C) and stored at –80°C. Transverse 8-µm serial sections were cut on a cryotome (Cryostat) at –26°C and mounted on slides for histochemical analysis of fiber type.

The contralateral soleus was dissected longitudinally into three sections and was placed in an ice-cold medium consisting of (in mmol/l) 10 EGTA-Ca-EGTA buffer (free Ca2+ concentration, 100 nM), 20 imidazole, 3 KH2PO4, 0.5 dithiothreitol, 20 taurine, 5.3 ATP, 15 phosphocreatine (PCr), 9.5 MgCl2, and 53.5 MES, pH 7.00. Fiber bundles in each section were separated with sharp-ended needles, leaving only small areas of contact, and incubated in 1.5 ml of the above medium (4°C) containing 50 µg/ml of saponin for 30 min with mild stirring. To completely remove saponin and metabolites, the fibers were washed three times with mild stirring for 5 min in 1.2 ml of a cooled (4°C) washing and oxygraph medium consisting of (in mmol/l) 10 EGTA-Ca-EGTA buffer (free Ca2+ concentration, 100 nM), 3 KH2PO4, 27 HEPES, 20 imidazole, 0.5 dithiothreitol, 20 taurine, 4 MgCl2, 74 sucrose, 5 pyruvate, 2 malate, 100 MES, and 2 mg/ml BSA, pH 7.00. After washing, the fibers were stored in the washing and oxygraph solution on ice until measurements of respiration were performed.

Measurements of mitochondrial respiration.   Mitochondrial oxygen consumption measurements were performed in a water-jacketed chamber maintained at 25°C. Oxygen consumption was monitored with a fiber-optic system (Instech model 210 fiber-optic oxygen monitor, Plymouth Meeting, PA) and a digital data-acquisition system (Ocean Optics, Dunedin, FL). Unlike a Clarke electrode, the fiber-optic system does not consume oxygen and is based on the phosphorescence quenching principle in which the oxygen concentration affects the rate of phosphorescent decay of the coated electrode tip. A bifurcated optic cable transmits the excitation light to the chamber probe and returns the resulting phosphorescence signal to the photo detector. Measurements were performed in 640 µl of the above-described washing and oxygraph solution. In all fibers, respiration was measured in the absence of ADP (V0) and after the sequential addition of 0.1 mM ADP (Vsubmax), 20 mM Cr (Vcreatine), and 1.5 mM ADP (Vmax). Immediately after respiratory measurements, the fiber bundles were removed, quick-frozen in liquid nitrogen, freeze-dried, and weighed. Wet weight was used as a reference for respiration and was obtained from the dry weight, by assuming 77% water content (2).

Fiber-type determination.   A modified procedure of Ogilvie and Feeback (19) was used to delineate the muscle fiber types. Sections were preincubated for 8 min in a medium containing 0.49% potassium acetate and 0.26% calcium chloride at pH 4.4 and then briefly rinsed in 0.1 M Tris buffer at pH 7.8. Sections were then incubated at room temperature for 30 min in a medium containing 0.4% glycine, 0.42% CaCl2, 0.38% NaCl, 0.19% sodium hydroxide, and 0.15% ATP at pH 9.4. Slides were rinsed with 1% CaCl2 and stained in 0.1% toluidine blue for 1 min, rinsed in distilled H2O, dehydrated in ethanol, cleared in Hemo-De, and mounted with Permount. Stained sections were viewed under a light microscope at x25 magnification. The entire muscle cross section was digitally imaged (each rectangular image being 1.15 mm x 0.86 mm). Images were stitched together in Photoshop (Adobe Systems, San Jose, CA), and type I and II fibers were counted.

Data analysis.   All values are presented as means ± SE. Differences between means were tested for statistical significance with a Student's t-test with significance set at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Exercise capacity.   At 11 wk of age, HCR rats (n = 8) ran 2,375 ± 80 m before exhaustion, compared with 238 ± 12 m for LCR rats (n = 8). Exercise time until exhaustion in HCR was 80.2 ± 1.6 vs. 17.9 ± 0.2 min for LCR.

Fiber type.   Because the intrinsic ADP and Cr sensitivity of mitochondrial respiration has been shown to be fiber-type dependent (16), one soleus muscle (randomized leg) was used to analyze fiber type (n = 6 HCR; n = 5 LCR). No differences between the two groups of rats were found, with the average percentage of type I fibers in the soleus being 87.2 ± 0.7%, similar to that found in other laboratories (5).

Mitochondrial function.   Permeabilized fiber bundles from HCR and LCR rats exhibited a high degree of respiratory coupling as indicated by a respiratory control ratio (the ratio of maximally ADP-stimulated respiration to noncoupled respiration) of 4.5 ± 0.3. Non-ADP-stimulated respiration (V0), submaximally ADP-stimulated respiration (Vsubmax), and maximally ADP-stimulated respiration (Vmax) were 13–18% greater in HCR, but they were not statistically different at the 5% level (Fig. 1). Similarly, mitochondrial sensitivity to ADP [ADP sensitivity; (Vsubmax – V0)/(Vmax – V0)] was not significantly different between groups (Table 1). Respiration in the presence of 0.1 mM ADP + 20 mM Cr (Vcreatine) was 33% higher (P < 0.01) in HCR compared with LCR (Fig. 1). Therefore, mitochondria from HCR rats demonstrated a significantly greater respiratory sensitivity to Cr [(Vcreatine – V0)/(Vmax – V0)] (Table 1).


Figure 1
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  		Fig. 1. Rates of respiration in permeabilized fiber bundles in the absence of ADP (V0), and after sequential additions of 0.1 mM ADP (Vsubmax), 20 mM Cr (Vcreatine), and 1.5 mM ADP (Vmax). w.wt., Wet weight. *P < 0.01 vs. low-capacity runners (LCR). HCR, rats with high intrinsic running capacity.

 

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  		Table 1. Sensitivity of mitochondrial respiration to submaximal concentrations of ADP in HCR and LCR rats

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The primary finding of this study is that despite similar oxidative capacity and training history of the soleus muscle, mitochondria from high-capacity runners demonstrated greater sensitivity for Cr-induced stimulation of submaximally ADP-stimulated respiration than low-capacity runners.

Mitochondrial oxidative capacity.   HCR rats exhibited 13% higher mean rates of both non-ADP-stimulated and maximally ADP-stimulated respiration that was not statistically significant. Although not a strict measure of mitochondrial density, comparisons of V0 per unit muscle mass at similar respiratory coupling ratios are indicative of mitochondrial density (4). Given that much larger changes in V0 have been reported after only 6 wk of training in human (35%) (36) and 4 wk of training in rat (55%) (4), the present data suggest there is little difference in mitochondrial density between groups and imply that factors other than large inherent differences in mitochondrial density were responsible for the enhanced exercise capacity of the HCR group.

ADP sensitivity.   It has previously been demonstrated that the sensitivity of the mitochondrion to ADP is fiber-type dependent and negatively correlated to training status (16, 30–32, 36). A lower ADP sensitivity in this context is not in regard to the whole muscle (which is dependent largely on mitochondrial density, and therefore, likely increased after training) but rather the sensitivity of the individual mitochondrion to ADP. Although seemingly contradictory to improved performance, it has been hypothesized that a decrease in mitochondrial sensitivity to ADP could be an adaptation to maintain normal resting [ADP] and rates of respiration despite the increased mitochondrial density that accompanies endurance training. However, the higher maximal oxidative capacity (mitochondrial density) of muscle, together with an exercise-induced increase in mitochondrial ADP sensitivity (via changes in PCr/Cr; see below), ensures that endurance trained muscle exhibits improved oxidative function during exercise (36, 37).

In the present study, ADP sensitivity averaged 0.15 ± 0.03, similar to that found in previous studies (35), and was nearly identical between groups (Table 1). As discussed above, measurements of V0 and respiratory control ratio imply a similar mitochondrial density between groups, supporting the hypothesis that ADP sensitivity is decreased in response to increased oxidative capacity. However, given that the training stimulus was minimal and identical between groups, it cannot be ruled out that some other exercise-related factor is responsible for setting the ADP sensitivity of the mitochondrion.

Cr sensitivity.   Mitochondria in slow-twitch mammalian muscle exhibit a decreased outer mitochondrial membrane permeability for ADP, leading to a Km for ADP that is over an order of magnitude higher than fast-twitch muscle (i.e., decreased ADP sensitivity) (16). However, PCr and Cr appear to easily pass over the outer mitochondrial membrane even in slow-twitch muscle. Therefore, in addition to providing a temporal energetic buffer, a secondary role for creatine kinase (CK) in slow-twitch muscle has been proposed on the basis of the localization of distinct isoforms of CK at the myofibril and/or sarcoplasmic reticulum (MM-CK) and the outside of the inner mitochondrial membrane (mi-CK) near the adenine nucleotide translocase (ANT). It is believed that functional coupling of these CK isoforms with ATPases and ANT results in the preferential formation of ATP at the myofibrils (14, 15, 20, 28) and ADP at the mitochondrion (12, 21, 23–26). According to the Cr shuttle hypothesis, it is thought that PCr and Cr, and not adenine nucleotides, are primarily shuttled between these two compartments (3, 12, 22, 23, 34). Therefore, alterations in cytosolic PCr-to-Cr ratio (PCr/Cr) will control, through interaction with mi-CK, the mitochondrial intermembrane concentration of adenine nucleotides in slow-twitch fibers.

During exercise the PCr/Cr is lowered, favoring the formation of ADP in the intermembrane space of the mitochondrion. It has previously been demonstrated in situ that changes in the [PCr] and [Cr] from those occurring at rest to those during high-intensity exercise can double the rate of mitochondrial respiration in the presence of an identical submaximal cytosolic [ADP] (37). Thus, during exercise, mitochondria become more sensitive to a given cytosolic [ADP] by the decrease in PCr/Cr that accompanies increased rates of work. In the present study, an increased ability of Cr to further stimulate respiration in the presence of a submaximally stimulating [ADP] was demonstrated in innate HCR rats, suggesting that ability of PCr/Cr to regulate mitochondrial respiration is enhanced. Therefore, it would be predicted that the mitochondria in HCR rats become progressively more sensitive to ADP than LCR rats as exercise intensity increases, minimizing the necessary cytosolic increases in [ADP] and [Pi]. Although mitochondrial density is an important factor in altering whole muscle sensitivity to ADP after endurance training, an increased sensitivity to PCr/Cr will have a similar effect by increasing the sensitivity of each mitochondrion to ADP during exercise. It can be speculated that part of the enhanced exercise performance demonstrated by HCR rats, despite similar local oxidative capacity, is the effect of this mechanism. Indeed, mi-CK has been demonstrated to increase after endurance training (1) and chronic stimulation (29). Furthermore, increased respiratory sensitivity to Cr has previously been reported as an adaptation to chronic training both in untrained (together with an increase in mitochondrial density) (36) and highly trained humans (with no change in mitochondrial density) (18, 36). These studies, together with the present data, suggest that mitochondrial sensitivity to Cr can play a fundamental role in determining exercise performance independent of alterations in local oxidative power.

The mechanism by which mitochondria from HCR muscle enhance sensitivity to Cr is unknown. However, the present data suggest that HCR rats exhibit an increased functional coupling of mi-CK to ANT. It has previously been shown that when mi-CK is dissociated from the inner membrane it exhibits roughly one-third of the activity of the structurally bound form (6, 24). Additionally, under conditions in which CK will dissociate from the membrane (increased Pi), Cr stimulated respiration has been shown to be reduced in permeabilized fibers from both cardiac (33) and skeletal (35) muscle. Therefore, in addition to the possibility of increased mi-CK content, it is possible that HCR rats maintain a higher degree of functional coupling between CK and ANT than LCR rats.

In conclusion, these results demonstrate that rats bred for high intrinsic running capacity exhibit an enhanced respiratory sensitivity to Cr. An increased sensitivity to Cr indicates a greater reliance on the PCr/Cr shuttle in propagating the signal for energetic demand to the mitochondria. This presumably results in an increased sensitivity of the mitochondrion, and thus whole muscle, to ADP during exercise despite similar fiber type, maximal oxidative power, and mitochondrial density and may contribute to the performance differences between HCR and LCR.


   FOOTNOTES
 

Address for reprint requests and other correspondence: B. Walsh, Univ. of California-San Diego, Dept. of Medicine, Physiology Div., 9500 Gilman Dr., MC0623A, La Jolla, CA 92093-0623 (e-mail: bjwalsh{at}ucsd.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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 DISCUSSION
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Reduced susceptibility to ventricular tachyarrhythmias in rats selectively bred for high aerobic capacity
Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2933 - H2941.
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 J. Appl. Physiol.Home page
J. A. Hawley and F. J. Spargo
It's all in the genes, so pick your parents wisely
J Appl Physiol, June 1, 2006; 100(6): 1751 - 1752.
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