Compared with the control SD-SED group, BV/TV was reduced by 41%, 51%, and 57% in the LCa-SED, HP-SED, and LCa/HP-SED groups, respectively. This BV/TV variation was related to a significant fall in both Tb.N and Tb.Th (a 17%-48% decrease), whereas Tb.Sp rose dramatically, that is, encompassing +59% and +157% (Table 3).
By comparing rat TR groups with each other, a 54%-65% drop in BV/TV was measured regardless of diet condition (LCa, HP, or HP/LCa diets; Fig. 1A), and the lowest BV/TV value was again reached with the most unbalanced diet (HP/LCa). Similar to SED group comparison data, Tb.N and Tb.Th decreased in TR groups for all modified diet conditions compared with control SD-TR (decrease from 15% to 59%), whereas a sharp Tb.Sp rise was underscored (variation: from +108% to +211%; Table 3).
Altogether, BV/TV changes are closely correlated with Tb.Th (r = 0.81, P < 0.001) and Tb.N (r = 0.76, P < 0.001) variations, regardless of training and diet conditions.
Therefore, to understand the origin of bone density decline, we analyzed the osteoblastic (Ob.S/BS) and osteoclastic (Oc.S/BS) surfaces in bone tissue from rats subjected to unbalanced diets. In SED groups, the LCa diet induces a significant 38% decrease in the Ob.S/BS, whereas Oc.S/BS remained unmodified (Figs. 1B and C). Contrariwise, both HP diets did not interact with Ob.S/BS, whereas Oc.S/BS was incremented by +75% and +62.5% for HP and HP/LCa diets, respectively (Figs. 1B and C). With Ob.S/BS and Oc.S/BS measurements, we also evidenced the beneficial effect of training on bone formation because training globally enhanced osteoblastic activity while reducing the osteoclastic activity (Figs. 1B and C). In addition, the greatest modification of Ob.S/BS was achieved with the HP diet (+49% rise when comparing HP-SED vs HP-TR), and the most critical alteration in Oc.S/BS was detected with LCa deprivation (−30% drop off comparing LCa-SED vs LCa-TR). As a further result, a positive correlation between Ob.S/BS and Tb.Th (r = 0.41, P < 0.01) was evidenced.
We also investigated the effects of training and unbalanced diets on adipocyte quantities in bones. The number of bone adipocytes dropped by 45% with training, only when animals were fed with balanced food (SD-SED vs SD-TR; Fig. 1D). Interestingly, modified diets combined with training had sizeable repercussions for adipocyte content. Indeed, regardless of the considered diet condition, a sharp increase in adipocyte numbers was demonstrated in TR groups, varying from +79% (HP-TR vs SD-TR) to +143% (LCa-TR vs SD-TR; Fig. 1D).
Dynamic parameters such as MS/BS, LGR, MAR, and BFR were measured to evaluate mineralization during the experiment using calcein labeling (Table 4).
For a considered diet condition, when comparing trained animals with the respective sedentary control (e.g., LCa-TR vs LCa-SED), training systematically expanded values of MAR, BFR, and MS/BS in a range varying between +7% and +64% (Table 4).
Two other noteworthy results were obtained when comparing SED or TR groups among each other. A significant decline of BFR was displayed when calcium deprivation was applied to the rats (SD-SED vs LCa-SED and SD-TR vs LCa-TR; Table 4). Similarly, HP-unbalanced diets (HP and HP/LCa) induced a significant LGR value reduction in SED and TR groups (Table 4).
In terms of correlations, positive correlations were observed between LGR and tibia length (r = 0.46, P < 0.005) or between MAR and Tb.Th (r = 0.47, P < 0.005). In addition, MS/BS was strongly positively correlated with Ob.S/BS (r = 0.78, P < 0.0001).
It is widely acknowledged that markedly unbalanced HP or LCa diets have sizeable repercussions for Ca2+, Pi, and PTH levels in blood serum. Because diets used in this study are moderately unbalanced in terms of phosphorus and calcium content, we analyzed the amounts of Ca2+, Pi, and PTH in the serum of our SED and TR rats (Table 5).
Under given dietary conditions, when comparing trained animals with their respective sedentary control, training induced a 13.7% Pi increase under low calcium conditions (LCa-SED vs LCa-TR), whereas the PTH level was reduced by about 45% when comparing SD-TR versus SD-SED and LCa-SED versus LCa-TR (Table 5).
Serum Ca2+, Pi, and PTH remained unaffected in the SED groups regardless of specific diet conditions. When comparing TR groups among each other, a slight but significant Ca2+ decrease was displayed when animals were fed with HP and HP/LCa diets (Table 5).
In addition, total proteins, pH, albumin, lactates, and free fatty acid levels were found to be unaffected by training and unbalanced diets (data not shown).
To conclude, when an unbalanced diet (0.35% Ca and/or 1.2% P) was supplied to animals, only slight modifications in our serum parameters were visualized.
In our study, the effects of training on rat bone tissue were investigated using a voluntary running wheel exercise. This method provides numerous assets: the absence of conditioning, the lack of noxious stimuli to impose running on the animals, and no environmental changes are required between running and nonrunning conditions. Moreover, this system allows the running exercise to occur mostly during the dark phase, in keeping with the normal nocturnal activity of rats. It further enables animals to eat and drink even during training phases. In some investigations on the basis of the effects of training on bone metabolism, training exercise was performed on treadmills. However, in our previously published results (12), we clearly demonstrated that the average distance covered by dark Agouti female rats proved greater in running wheels (up to 50 km·wk−1) as compared with common standards recorded in treadmills (up to 8 km·wk−1). In the same study, we also showed that a 4-wk voluntary exercising was sufficient to induce a bone mass increase in growing rats. Furthermore, Lambert and Noakes (23) made the following recommendation: rats that spontaneously ran at least 11.6 km·wk−1 over an approximately 2-month period were considered to have undergone a training effect. On account of such parameters, we preferred the use of running wheels rather than treadmills to ensure an efficient 6 wk of running training lapse in our study herein.
Gross bone parameters.
In our sedentary rats, only high-phosphorus diets (both HP and HP/LCa diets) induced a reduction in tibiae wet weight. We also observed that the negative effect on this parameter is incremented when the excess of phosphorus is combined with calcium deprivation (HP/LCa diet). This is consistent with data previously described in the literature. Indeed, as reviewed by Calvo (4), high phosphorus intake induced progressive bone loss in various mammalians such as mice, rats, rabbits, horses, cats, pigs, and dogs. As shown by Bauer and Griminger (2), a high-phosphorus diet (1.2% phosphorus) decreased atlas bone density in young female rats, and the detrimental effects of an HP diet on long bones are even more prominent when the diet also contains a low quantity of calcium (0.3% calcium).
In the literature, low-calcium diets have been reported to reduce strength (6), density (25,31), and mineral content (7) of bones in sedentary young or adult rats. In our present experiment, calcium deprivation in sedentary rats did not modify gross tibiae parameters. The apparent discrepancy between our results and the existing data to date could result from either the nature of the considered bone (tibiae, femur, or ulna) or the exact bone site localization for measurements or yet again the level and duration of calcium restriction. Indeed, within our experiment, macroscopic bpme analyses have been performed on the whole tibiae, whereas in most studies published to date, these measurements were confined to more discrete bone regions such as the shaft and proximal or distal metaphysis. For example, calcium restriction (0.2% calcium) induced a reduction of bone mineral density in rat bone proximal metaphysis but remained unmodified in the distal metaphysis and shaft (42). In terms of calcium deprivation level, it has been shown that a low calcium quantity ranging from 0.03% to 0.18% reduces bone strength and bone density in young growing rats (31). Because the level of calcium restriction is at 0.35% in our study, it is therefore conceivable to detect only slight variation in bone weight parameters.
Six weeks of training enlarged all measured gross tibiae parameters (length and wet, dry, or ash weights) regardless of diet conditions. These results are congruent with previously published data. Exercised rats exhibited a cortical bone mass increase (dry and ash weights) as compared with sedentary counterparts (29). Positive training effects on gross parameters are also recovered in trained rats fed with all modified diets to a lesser extent however. This suggests that unbalanced food is detrimental to the benefit of training brought in terms of gross bone parameters.
It is widely acknowledged that physical training induces an increase in bone mechanical properties in both humans (10) and rats (17). Bone mechanical properties depend not only on the amount of bone mass but also on its trabecular bone microarchitecture. A constant turnover in lamellae remodeling (number, thickness, spatial distribution) contributes to optimal bone structure and mechanical properties (19). The constant evolution of trabecular bone microarchitecture is mainly regulated by a tight balance between two cellular activities: the osteoblastic and osteoclastic activities responsible for bone formation or bone resorption, respectively. We therefore analyzed both trabecular static and dynamic parameters in sedentary and exercised rats whether subjected or not to unbalanced diets. In rats fed with standard food, training enhances bone trabecular density in the cancellous metaphyseal area (Tb.N, Tb.Th, and BV/TV increment associated with a Tb.Sp reduction) by increasing the osteoblastic surface and decreasing the osteoclastic surface. For sedentary rats fed with unbalanced diets, either calcium restriction or excess phosphorus induces a loss of bone trabecular density (Tb.N, Tb.Th, and BV/TV decline correlated with a Tb.Sp rise). The most detrimental values were obtained with the most unbalanced diet (HP/LCa diet). Interestingly, this fall in trabecular density is only due to a drop in the osteoblastic surface in LCa diet animals, whereas an amplification of the osteoclastic surface is responsible for the trabecular density reduction in HP and HP/LCa diet rats. When training was combined with unbalanced diets, it provides a beneficial effect on bone microarchitecture in all food conditions. However, bone trabecular density parameters do not reach the values obtained with SED rats fed with normal food. In addition, dynamic parameters related to calcein injections confirmed that training enhances the quantity of newly mineralized bone in the cancellous metaphyseal area regardless of the kind of food (standard or unbalanced diet).
To our knowledge, our study herein provides an innovative as well as comprehensive analysis regarding the combined effects of voluntary wheel training and various unbalanced calcium/phosphorus diets on bone turnover. Indeed, using extensive static and dynamic histomorphometric parameters, our results highlight the basic cellular mechanisms involved in bone mass regulation in the rat model combining unbalanced diet and training conditions. This investigation is consistent with previously published data related to the influence of training and unbalanced food on rodent bone tissue.
In terms of training span, 4-wk running wheel training was associated with an increase in osteoblastic bone formation, whereas osteoclastic activity remained unaffected (12). In our present study, we clearly demonstrated that running wheel training over a 6-wk period is also associated with an osteoblastic bone formation increase concomitantly, however, with an osteoclastic resorption decline. The discrepancy between these results in the involvement of osteoclastic activity could be explained by the different physical training time allowances. Interestingly, Yeh et al. (43) showed that 6-wk treadmill exercise increased bone formation in young rats while triggering decreased bone resorption, a finding that is consistent with our present investigation. For dynamic parameters, young growing rats subjected to treadmill exercises exhibited expansion of MAR and BFR in both the distal and the proximal tibial metaphyses after 8 wk of training (15). This is also congruent with our results herein.
Concerning unbalanced diet influence, there is substantial evidence that LCa restriction is able to induce a decline of tibial trabecular density (Tb.N and BV/TV) in young and adult rats (32,36). In young rats, this detrimental effect on static parameters is associated with dynamic parameter attenuation, such as MAR and BFR (32), similar to our findings herein related to LCa deprivation. Contrariwise, in adult rats fed with food containing as little as 0.1% calcium (compared with 0.35% in our investigation and 0.25% in the study of Peterson et al. ), MAR and BFR remained unmodified despite the drop in BV/TV and Tb.N (36). This would suggest that there is no change in adult rat bone turnover (unchanged calcein labeling) even when the animals are subjected to high-calcium restriction, whereas in young rats, even a moderate LCa diet can produce bone turnover modification. Thus, it can be hypothesized that growth present in young rats but absent in older rats would be responsible for the drop in mineralization surface and related change in bone turnover.
When an HP diet is provided to young male rats, Huttunen et al. (13) have demonstrated through microcomputing tomography a BV/TV drop and a Tb.Sp rise in tibiae, whereas Tb.N and Tb.Th remained unchanged. This modification in static bone trabecular density is correlated with a reduction of bone strength as assessed by mechanical load deformation testing. In addition, osteoclast numbers were enlarged in the femur of rats fed a 1.2% HP diet (13). Such results are congruent with our data except for Tb.N and Tb.Th, which are significantly increased in our 1.2% HP diet rats, thus providing further evidence regarding bone weakness after an HP-unbalanced diet.
To our knowledge, only one investigation has focused on the effects of unbalanced diets in combination with exercise on bone trabecular parameters (42). Using microcomputing tomography measurements, a 0.2% LCa diet induced a weak but significant 7% reduction of BV/TV in the proximal ulna of young sedentary female rats. When high-impact exercise is combined with LCa restriction, a 17% BV/TV increase was obtained, indicating that the positive effect of training can counterbalance the detrimental influence of an LCa diet (42). In our present experiment, the sizeable 41% drop in BV/TV provoked by a 0.35% LCa diet in tibial cancellous area cannot be fully compensated for by wheel running exercise (+35% BV/TV improvement). However, in our study, the negative effect of calcium restriction on BV/TV in tibial metaphysis is more pronounced than the one measured by Welch et al. (42) in proximal ulna. Therefore, we may hypothesize that physical training is prone to counterbalancing weaker bone trabecular density defects rather than more important ones.
Nowadays, it is common knowledge that in the bone marrow stromal environment, adipocytes and osteoblasts derive from a common mesenchymal stem cell (MSC) (33). We previously demonstrated that the decline in the osteoblastic surface observed in tibiae of the unloaded rat model was concomitant with a rise of adipocyte numbers (1). This phenomenon was due to a reduction in osteoblast progenitors (27) combined with an enlargement of adipocyte precursor cells (1), resulting from a reorientation of MSC in bone marrow stroma. Contrariwise, climbing exercise enhanced osteoblast differentiation and inhibited the adipogenic one (28). In our present investigation, wheel running training performed with rats fed with standard food induced a drop on adipocyte numbers associated with an enlargement of Ob.S/BS in tibial metaphyseal bone marrow. Such a result is congruent with the ones published by Menuki et al. (28). When rats were fed with unbalanced diets (LCa, HP, and HP/LCa), training did not exhibit a negative influence on the adipocyte number. Contrariwise, in the present study, the quantity of adipocyte was substantially enhanced. Such an observation implies that inappropriate calcium and/or phosphorus intakes could alter the orientation of MSC differentiation toward the adipogenic pathway. Recently published in vitro experiments corroborated our hypothesis (18,26). Indeed, MSC continuously exposed to a high Ca2+ concentration inhibited preadipocyte differentiation (18), whereas calcium restriction or Pi supplementation in MSC cultures had negative effects on MSC proliferation and osteogenic differentiation (26).
Our present data clearly indicate that training and unbalanced calcium/phosphorus diets have tremendous repercussions for tibial trabecular microarchitecture. Hence, it proved relevant to address the issue as to whether such conditions could have consequences on the regulation of calcium and phosphorus content in blood serum. In addition, calcium homeostasis is tightly regulated by PTH (39). Therefore, we measured Ca2+, Pi, and PTH levels in serum of our sedentary or trained rats whether subjected or not to various unbalanced diets. Generally, all diets tested in sedentary rats did not modify serum Ca2+, Pi, or PTH levels. In rats fed with standard food, only the PTH level is affected by training (−45% reduction).
The effects of training on serum PTH levels have been already reported in reference literature as regards young female growing rats after 7 or 11 wk of treadmill exercise (14). Authors have argued that training stimulated bone formation, resulting in an increased requirement for minerals. This was satisfied by an increase in intestinal absorption of Ca2+ via 1,25-dihydroxyvitamin D3 activity. Subsequently, they speculated that in return, this increase in Ca2+ absorption reduced the serum PTH level in an attempt to regulate serum homeostasis. This hypothesis could also account for our PTH level results obtained in our rat model of running wheel training.
Interestingly, excess in terms of phosphate (1.2% phosphorus) or calcium restriction (0.35% calcium) in our sedentary rats did not modify PTH levels. Usually, in more unbalanced diets, low calcium conditions (31) or excess phosphorus (13) triggered PTH level augmentation (37). On the basis of these investigations, the approximate threshold generating a change in PTH levels was then 0.25% for calcium deprivation (37) or 1.5% for excess phosphorus (38). To sum up, for the first time, our study demonstrated that a mild calcium- or/and phosphorus-unbalanced diet in rodents is able to generate important modifications in bone trabecular microarchitecture without the activation of the complex regulation mechanisms of bone mineral homeostasis.
To conclude, our unbalanced calcium and/or phosphorus diets administered to rats had slightly negative effects on gross tibia parameters (bone weight, bone mineral content). Such diets, however, exerted a highly detrimental effect on tibial metaphyseal trabecular microarchitecture. Thus, it is noteworthy that the origin of bone alteration relies on the nature of the diet. Indeed, calcium restriction preferentially reduces bone formation, whereas high phosphorus intake fosters significant bone resorption. Interestingly, despite important losses in bone trabecular microarchitecture, our unbalanced diet did not alter serum bone mineral homeostasis.
Whenever training was combined with unbalanced calcium and/or phosphorus diets, physical exercise exerted global positive effects on both gross tibia parameters and trabecular architecture. Training also attenuates bone formation or resorption disturbances generated either by calcium deprivation or excess phosphorus, respectively. Nevertheless, training benefits did not suffice to fully compensate for detrimental dietary effects on bone turnover.
Our rat model on the basis of young animals subjected to unbalanced diets was chosen to mimic unhealthy food encountered worldwide among young human populations (24). By extending our present results to young adult consumers of inappropriate food leading to unbalanced calcium and phosphate intakes (low milk consumption and soda drinks and preservatives overconsumption), serious ultrastructural bone alterations could be expected in this population, optimizing thereby the risk for bone fractures. Hence, the issue of counteracting unhealthy dietary patterns among teenagers as early as possible stands out as a leading health issue. Indeed, our study provides hereby substantial evidence to the effect that higher calcium intake after young adulthood fails to offset the detrimental effects of either calcium restriction or phosphorus overconsumption during adolescence on peak bone mass (21). According to our results gathered from the rat model, regular physical exercise during young adult growth is prone to partially counterbalance the deleterious effects of an unbalanced diet on bone tissue. This assertion remains to be verified in young humans known to eat food enriched in phosphorus (soft drink consumption) and restricted in calcium (absence of cheese and milk). Bone metabolism could be analyzed in this population whether subjected or not to well-balanced food and subdivided into sedentary or athletic groups.
This work was supported by a grant from the U.S. Army (DAMD-17-02-1-0220 to Dr. Erik Zerath).
The authors thank Mrs. Marine Le Drast and Dr. Frances Ash for their language assistance and Dr. Patrice Le François for the elaboration of unbalanced diets.
The results of the present study do not constitute endorsement by the American College of Sports and Medicine.
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Keywords:©2011The American College of Sports Medicine
PHYSICAL TRAINING; WHEEL RUNNING; AGOUTI RAT; BONE MASS; NUTRITION; BONE REMODELING