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* Department of Animal Sciences and
** Division of Nutritional Sciences, University of Illinois, Urbana, IL 61801 and
Animal Disease and Diagnostic Laboratory, Purdue University, West Lafayette, IN 47907
4To whom correspondence should be addressed. E-mail: rwjohn{at}uiuc.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • cytokines • growth • infection • protein accretion • myostatin
Pathogens that infect a host induce an inflammatory response that involves the synthesis and release of metabolically active cytokines such as IL-1ß, IL-6, and TNF
. These inflammatory cytokines reduce appetite and food intake (FI),5 inhibit nutrient absorption, increase metabolic rate, and alter nutrient utilization in a tissue-specific manner (1). Consequently, macro- and micronutrient deficiencies can occur, which may aggravate the initial disease and facilitate infection by secondary pathogens. One of the most dramatic metabolic effects of acute and chronic infection occurs in skeletal muscle, where protein synthesis is impaired and protein degradation is enhanced (2,3). In severe cases, as in sepsis, there is a net loss of whole-body protein accompanied by weight loss. In other cases, body weight (BW) and protein accretion (PA) may continue to increase, but at a slower rate (4). The latter condition is reminiscent of what occurs in young calves (5) and pigs (4) with chronic infections. Not surprisingly, the incidence of infection and the level of growth depression in these farm animals are often closely related to the sanitary condition of the environment in which they are housed. In any case, the composition of growth during an ongoing infection has not been determined in rapidly growing animals, nor have the physiologic mechanisms that underlie the depressed growth. A more thorough understanding of how infection affects growth should help elucidate nutritional needs.
To this end, for this study young pigs were kept in disease-containment chambers and experimentally infected with Mycoplasma hyopneumoniae (Mh) and/or Porcine Reproductive and Respiratory Syndrome Virus (PRRSV). These microorganisms infect the respiratory system and are commonly isolated from pigs with porcine respiratory disease complex, an emerging multifactorial respiratory syndrome characterized by reduced FI and slow growth (6). The objectives were to determine the effects of these pathogens on FI, whole-body composition, and PA and to determine the relation between serum cytokines and growth. We further sought to determine whether infection increased the steady-state level of myostatin (MSTN) mRNA in skeletal muscle. MSTN is a negative regulator of muscle mass (7) and is reportedly elevated in several conditions characterized by inflammation and muscle wasting (8,9). An increase in MSTN might partially explain why infection inhibits growth.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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At 3 wk of age, 40 pigs in each of the trials were divided into 10 uniform blocks of 4 pigs each based on litter of origin, BW, and gender and randomly assigned from within blocks to 1 of 4 treatments, which were imposed in 2 suites of 8 disease-containment chambers (16 chambers in all) that we described elsewhere (10). Two pigs (1 castrated male and 1 female) were placed in each chamber and the 8 remaining pigs in each trial were killed (sodium pentobarbital at 1.1 g/kg BW i.v.) to verify the absence of gross pulmonary lesions indicative of mycoplasmal pneumonia. After a 1-wk acclimation period, treatments were imposed in the remaining 32 pigs. Pigs were maintained under an 18-h light:6-h dark lighting regimen (lights on at 0600 h) and were provided free access to water and food unless otherwise stated. A commercially available diet (10) provided adequate to superadequate levels of all essential nutrients (11). Chamber temperature was maintained at 32°C for the first 2 wk after pigs arrived and was then reduced 2° each week until the desired temperature of 24°C.
Experimental procedures. For Mh inoculation, 4-wk-old pigs were anesthetized by i.m. injection of telazol:ketamine:xylazine solution (2:1:1; 4.4 mg/kg BW). Pigs in one-half of the chambers (i.e., 16 pigs in 8 chambers per trial) were inoculated intratracheally with 3 mL of Mh (strain P5722-3, broth containing 1010 color-changing units/L). Pigs in the remaining chambers received 3 mL of sterile Friis medium intratracheally. Two wk later, pigs in one-half of the chambers that received sterile Friis medium (i.e., 8 pigs in 4 chambers per trial) were given 5 mL of sterile DMEM (control) intranasally, whereas the other half were inoculated intranasally with 5 mL of a high-virulence strain of PRRSV (ATCC VR-2385 isolate P-129 containing 105 50% tissue culture infected dose). Pigs in half of the chambers that had received Mh received 5 mL of sterile DMEM (Mh), whereas the other half were inoculated intranasally with 5 mL of PRRSV (Mh + PRRSV). The timing of PRRSV inoculation was chosen to coincide with the onset of clinical signs of mycoplasmal pneumonia (10,12). Biosafety Level 3 procedures were employed at all times to avoid cross contamination. The University of Illinois Institutional Animal Care and Use Committee and the Environmental Health and Safety Committee approved all procedures.
Body weight was measured immediately before Mh inoculation and every 7 d thereafter. To minimize variation in pig BW due to feeding, feeders were removed 12 h prior to all weighings. Feeders were weighed weekly after Mh inoculation and daily after PRRSV inoculation between 0800 and 0900 h so that food intake could be estimated.
In each of the 2 trials, 2 chambers of control, Mh, PRRSV, and Mh + PRRSV pigs were killed at 7 or 14 d after PRRSV inoculation. Upon killing, lungs were inspected for gross lesions, defined as purple to grayish-purple, firm, sunken, and well-defined areas of consolidation. The edge of each lesion was sketched on standard drawings as previously described (10) and the percentage of gross pulmonary lesions was quantified using imaging analysis (13). Tissue samples taken from the ventral margin of the cranial and middle lung lobes were placed on ice and later stained with an immunofluorescent antibody against Mh to determine the presence or absence of Mh (14). Virus isolation procedures were used to detect the presence or absence of PRRSV in serum collected just prior to killing.
Whole-body compositional analysis. Procedures for determining whole-body composition and PA were described in detail elsewhere (10). In short, whole-body was homogenized and samples were stored at –80°C. Samples were later weighed, freeze-dried, and analyzed for dry matter (DM), protein, lipids, and ash content. Procedures to determine whole-body PA were similar to those used by Chung and Baker (15). Whole-body composition on the day of PRRSV inoculation was estimated based on BW using regression equations developed from a previous study that involved pigs of the same genetic background, from the same swine herd, and that were maintained under the same environmental and experimental conditions (10).
Ribonuclease protection assay (RPA). The forelimb muscle triceps (T) and the hind limb muscle biceps femoris (BF) were dissected and weighed, and a tissue sample was collected and frozen in liquid nitrogen and stored at –80°C for MSTN mRNA analysis using a typical RPA procedure that we previously described (10). The partial cDNA fragment for porcine MSTN was provided by Dr. Matthew B. Wheeler (Department of Animal Sciences, University of Illinois). The cDNA fragment for 18S was purchased from Ambion, and used as an internal reference. The full-length probes for MSTN and 18S were 802 and 128 nucleotides (nt), respectively; the protected fragments were 707 and 80 nt, respectively. The relative radioactive intensity of each band was quantified by phosphorimage analysis (Molecular Dynamics).
Skeletal muscle myofibers. Samples obtained from the BF and T muscles of control and PRRSV pigs were fixed in 10% neutral formalin, dehydrated, and embedded in paraffin, and 5-µm-thick sections were obtained on a microtome (American Optical). Sections were mounted on glass slides and stained according to the trichrome stain protocol (Sigma). Myofibers within a 22,500-µm2 area were counted using a light microscope (Nikon Eclipse E400). The myofiber cross-sectional area was determined from myofiber counts obtained from 3 different areas of each muscle.
Plasma cytokines. The inflammatory cytokines IL-1ß and IL-6 were measured in serum collected from pigs just prior to killing 7 d after PRRSV inoculation. Commercially available ELISAs specific for porcine IL-1ß and IL-6 (both from R&D Systems) were used as previously described (16).
Statistical analysis. The GLM procedure of SAS was used for randomized complete-block designs with a 2 x 2 factorial treatment arrangement. An individual pig was considered the experimental unit for weight gain (WG), whole-body composition, protein, lipid, and ash accretion, circulating inflammatory cytokines, muscle weight, cross-sectional area of myofibers, and steady-state levels of MSTN mRNA in muscle. The chamber (i.e., 2 pigs) was considered the experimental unit for assessment of FI and gain:food ratio. Slope-ratio analysis was used to compare multiple linear regression PA curves of PA vs. time (17). Least-squares means were compared using a t test and Fisher adjustment by the PDIFF option of SAS. Data are means ± SEM. Differences were considered significant at P < 0.05.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Gross lung lesions were not present postmortem in control or PRRSV pigs (Fig. 1) and in those pigs killed at allotment (data not shown). Gross lung lesions were found in Mh pigs 7 and 14 d after PRRSV inoculation (i.e., 21 and 28 d after Mh inoculation, respectively; P < 0.001). The Mh-induced lesions were exacerbated by PRRSV at both times (P < 0.001).
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Whole-body composition. Neither a significant main effect of Mh nor an interaction between Mh and PRRSV was found for any measured component. Therefore, the data from control PRRSV– and PRRSV+ were pooled for statistical analysis. The whole-body concentrations of lipids, protein, and ash are expressed on a DM basis (Table 2). After 1 wk of PRRSV infection, the concentration of DM and lipids decreased (P < 0.01), whereas protein and ash concentrations increased (P < 0.01) in PRRSV+ pigs compared to PRRSV– pigs. These differences in whole-body composition were further exacerbated after 2 wk. These findings indicate that PRRSV+ pigs were leaner than PRRSV– pigs.
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The effects of PRRSV infection on the composition of growth were also examined by comparing pigs with a similar body weight but that were either PRRSV– or PRRSV+. The BW of PRRSV– pigs after 7 d was similar (P = 0.74) to that of PRRSV+ pigs after 14 d. Nevertheless, PRRSV+ pigs at 14 d had a lower (P < 0.001) concentration and amount of DM and lipids and a higher (P < 0.001) concentration of protein and ash, but levels of protein and ash that did not differ from PRRSV– pigs at 7 d (P = 0.26).
Whole-body protein, lipid, and ash accretion. The amount of whole-body protein, lipid, and ash accreted (g/d on a DM basis) did not differ between control and Mh pigs (data not shown). This finding is consistent with a previous study (10). Similarly, accretion of lipids and ash did not differ between PRRSV and Mh + PRRSV pigs (data not shown). Thus, PRRSV was solely responsible for the observed changes in the accretion of body components (Table 3). The relative amount of protein deposited daily in the body tends to decrease as animals grow. In our study, PRRSV+ pigs reduced PA by 56.1% between wk 1 (d 0–7) and wk 2 (d 7–14) of the experiment compared to only 21.2% in PRRSV– pigs. Further, PRRSV+ pigs accreted less (P < 0.001) protein during wk 1 (59.1%) and wk 2 (32.9%) of the experiment compared to PRRSV– pigs. Moreover, slope-ratio analysis of multiple linear regression curves indicated that daily PA was lower in PRRSV+ pigs compared to PRRSV– pigs throughout the 14-d trial (49.0 vs. 110.3 ± 6.9 g/d, respectively). Thus, each day after inoculation with PRRSV, pigs accreted 55.6% less (P < 0.001) protein during the 14-d trial. Pigs infected with PRRSV also reduced ash accretion by 78% between wk 1 and 2 of the experiment compared to 35% in PRRSV– pigs. The reduction in lipid accretion between wk 1 and 2 of the study was most profound in PRRSV+ pigs. In fact, PRRSV+ pigs did not accrete lipids during wk 2 of the study (Table 3).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Mh in swine is restricted to the respiratory system where it adheres to the surfaces of the trachea, bronchi, and bronchioles. It causes a localized inflammatory response, which contributes to the development of gross pulmonary lesions and chronic pneumonia (18). PRRSV, however, infects alveolar macrophages (19) that migrate to regional lymphoid tissue and to circulation and monocytes. Cells infected with PRRSV produce inflammatory cytokines (20,21) and are eventually destroyed by the virus through necrosis (22) or virus-induced apoptosis (23), rendering the pig immunosuppressed. In our study, this was evident by the marked increase in circulating IL-1ß and IL-6 observed 7 d after PRRSV inoculation and the fact that Mh was allowed to spread rampantly throughout the lungs when PRRSV was present.
Inflammatory cytokines act on a number of physiological systems affecting growth [e.g., food intake regulation and growth hormone insulin-like growth factor I (IGF-I) axis] (24). Therefore, PRRSV infection, which increased serum levels of IL-1ß and IL-6, profoundly affected FI, WG, PA, and whole-body composition whereas Mh infection did not. To shed light on the impact of food intake on growth, WG and PA were corrected by FI in a covariance analysis. The reduced FI observed in PRRSV-infected pigs largely explained the decrease in WG. This finding was not unexpected in that PRRSV-infected pigs were as efficient as uninfected control pigs at converting food to body WG. The decrease in PA of PRRSV-infected pigs, however, was not explained entirely by the reduction in FI. For the 14-d period after PRRSV inoculation, after adjusting for FI, PA was significantly reduced in PRRSV+ pigs compared to PRRSV– pigs (105.9 vs. 76.8 ± 7.4 g/d, respectively). In other words, this analysis suggests that if PRRSV– pigs and PRRSV+ pigs consumed the same amount of food and had a comparable WG, PA would have still been lower in PRRSV-infected pigs. However, a study that includes an uninfected group, pair-fed to PRRSV-infected pigs, is needed to verify this conclusion. Nonetheless, we interpret the covariate analysis to suggest that the systemic inflammatory response altered metabolic processes in disparate tissues. Cytokines act directly on skeletal muscle (25) to reduce the efficacy of anabolic hormones such as IGF-I and insulin (26). In addition, cytokines can directly reduce the rate of skeletal muscle protein synthesis (27,28) and enhance the rate of skeletal muscle protein degradation (29,30) with the net result of reduced PA.
Growth differentiation factor-8 (i.e., MSTN) is a member of the transforming growth factor-ß superfamily of secreted growth and differentiation factors. MSTN is known to negatively regulate muscle mass in both mice (7,31) and cattle (32,33). Moreover, increased MSTN was reported in men with AIDS-wasting syndrome (8), in cardiomyocytes surrounding an infarct area (34), and in necrotic fibers of the BF muscle of rats (35). Thus, a current hypothesis is that MSTN may act as a muscle "chalone," a circulating factor that promotes or inhibits the growth of a specific tissue and thereby maintains its appropriate mass (36). Recent studies strongly support the idea that MSTN acts as a postnatal muscle chalone in mammals (37,38). In our study, we found a coincidental elevation in steady-state levels of MSTN mRNA in muscle of pigs with elevated circulating inflammatory cytokines and reduced PA.
The promoter region of the human MSTN gene contains 2 nuclear factor-
B and 12 glucocorticoid transcriptional response elements (39). Thus, inflammatory cytokines may activate MSTN transcription directly via nuclear factor-B activation or indirectly through glucocorticoid release. Indeed, dexamethasone increases MSTN mRNA in murine C2C12 myotubes (39). In addition, pretreatment of rats with the glucocorticoid receptor antagonist RU486 prevented the increase in MSTN mRNA and the concomitant decrease in gastrocnemius protein content observed in thermal injury and dexamethasone injection (9). In the present study, we measured cortisol in plasma samples collected 7 d after PRRSV inoculation and found no differences among treatments. Interpreting these results is problematic, however, because cortisol levels fluctuate over the course of an infection. Much more work is needed to assess the role of glucocorticoids in MSTN expression during infection.
Another important effect of inflammatory cytokines is reduced appetite. A reduction in the availability of nutrients for muscle growth was shown to induce MSTN expression. In one experiment, 4- and 7-wk-old piglets were food-deprived for 3 d and MSTN mRNA was measured in longissimus dorsi muscle (40). Short-term food deprivation had no effect on MSTN mRNA. Long-term underfeeding, however, increased MSTN mRNA in the longissimus dorsi muscle. Lambs were allowed to consume food ad libitum or fed at 30% maintenance (underfeeding) for various periods of time ranging from 1 to 22 wk (41). Underfeeding caused an increase in MSTN (mRNA and protein) in the semitendinosus muscle with a concomitant decrease in the mRNA levels of IGF-I and the myogenic regulatory factors Myf-5, MyoD, and myogenin. When sheep that were underfed for 22 wk were refed, MSTN protein rapidly decreased and IGF-I, Myf-5, MyoD, and myogenin increased. Collectively, these studies suggest that short-term reduction in FI does not impact MSTN expression but long-term reduction in FI does. In our study, 12 h of food deprivation prior to killing probably had no effect on MSTN mRNA. However, the sustained reduction in FI observed in PRRSV-infected pigs may have contributed to the increased MSTN in skeletal muscle. Thus, a cytokine-mediated reduction in FI during disease may indirectly induce MSTN expression, which inhibits growth and therefore the utilization of nutrients by growing muscle.
We conclude that in young pigs the magnitude of increases in inflammatory cytokines during acute respiratory infection may be predictive of decreases in PA and growth. We further suggest that growth of skeletal muscle during infection is limited in part by MSTN. These results help explain growth inhibition of pigs with chronic infections, but may also shed light on the mechanisms underlying decreased WG and linear growth of animals and human children under similar circumstances.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Recognized with the 2002 National Pork Board Award for Innovation in Research at the Midwestern Section of the American Society of Animal Science Meeting, Des Moines, Iowa (Abstract: Protein Accretion in Pigs Infected with Mycoplasma hyopneumoniae and Porcine Reproductive and Respiratory Syndrome Virus; Escobar, J., Toepfer, T. L., Van Alstine, W. G., Baker, D. H. & Johnson, R. W.); and was a finalist in the 2002 American Society of Nutritional Sciences Proctor & Gamble Graduate Student Research Award (J.E.) at the Federation of American Societies for Experimental Biology Annual Meeting, New Orleans, LA. (Abstract: Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) but not Mycoplasma hyopneumoniae (Mh) Decreases Protein Accretion and Markedly Increases Skeletal Muscle Myostatin (MSTN) Gene Expression in Young Pigs; Escobar, J., Toepfer, T. L., Van Alstine, W. G., Baker, D. H. & Johnson, R. W.).
3 Current address: USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics-Nutrition, Baylor College of Medicine, Houston, TX 77030.
5 Abbreviations used: BF, biceps femoris; BW, body weight; DM, dry matter; FI, food intake; IGF-I, insulin-like growth factor I; Mh, Mycoplasma hyopneumoniae; MSTN, myostatin; nt, nucleotide; PA, protein accretion; RPA, ribonuclease protection assay; PPRSV, Porcine Reproductive and Respiratory Syndrome Virus; PRRSV+, PRRSV and Mh + PRRSV pigs; PRRSV–, control and Mh pigs; T, triceps; WG, weight gain.
Manuscript received 4 June 2004. Initial review completed 14 July 2004. Revision accepted 10 August 2004.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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