Biomedical subjects

Charlotte A Peterson

Publications and source records attributed to Charlotte A Peterson.

At least 19 recordsLinked to original sources

PubMed2006

Nuclear translocation of EndoG at the initiation of disuse muscle atrophy and apoptosis is specific to myonuclei.

Skeletal muscle atrophy is associated with an increase in apoptosis, and we showed previously that endonuclease G (EndoG) is localized to nuclei following unloading. The goal of this study was to determine whether the onset of apoptosis in response to disuse was consistent with the hypothesis that EndoG is involved in myofiber nuclear loss. Atrophy was induced by hindlimb suspension for 12 h or 1, 2, 4 and 7 days in 6-mo-old rats. Soleus myofiber cross-sectional area decreased significantly by 2 days, whereas muscle mass and muscle-to-body mass ratio decreased by 4 and 7 days, respectively. By contrast, a significant increase in apoptosis, evidenced by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive nuclei, occurred as early as 12 h after suspension, preceding the elevation in muscle atrophy F-box gene expression. The early increase in apoptosis appeared to be specific to myofiber nuclei, whereas TUNEL-positive interstitial cells did not become significantly elevated until 2 days after suspension. Furthermore, TUNEL-positive myofiber nuclei colocalized with EndoG as early as 12 h after suspension, and no such localization was observed in interstitial cells. Although no significant change in total activated caspase-3, -7, or -12 protein abundance was apparent, activated caspase-3 was expressed in interstitial cells undergoing apoptosis, some of which were endothelial cells. These data indicate that apoptosis is an early, and therefore possibly causative, event in the process of muscle atrophy, and that EndoG nuclear translocation is specific for myofiber nuclear apoptosis, whereas interstitial cells may undergo apoptosis via a more classical, caspase-dependent pathway.

Active Transport, Cell Nucleus↗

PubMed2006

Pioglitazone induces apoptosis of macrophages in human adipose tissue.

Metabolic syndrome and type 2 diabetes mellitus are associated with an increased number of macrophage cells that infiltrate white adipose tissue (WAT). Previously, we demonstrated that the treatment of subjects with impaired glucose tolerance (IGT) with the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist pioglitazone resulted in a decrease in macrophage number in adipose tissue. Here, adipose tissue samples from IGT subjects treated with pioglitazone were examined for apoptosis with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. TUNEL-positive cells were identified, and there was a significant 42% increase in TUNEL-positive cells following pioglitazone treatment. Overlay experiments with anti-CD68 antibody demonstrated that most of the TUNEL-positive cells were macrophages. To determine whether macrophage apoptosis was a direct or indirect effect of pioglitazone treatment, human THP1 cells were treated with pioglitazone in vitro, demonstrating increased TUNEL staining in a dose- and time-dependent manner. Furthermore, the appearance of the active proteolytic subunits of caspase-3 and caspase-9 were detected in cell lysate from THP1 cells and also increased in a dose- and time-dependent manner following pioglitazone treatment. Pretreatment with a PPARgamma inhibitor, GW9662, prevented pioglitazone induction of the apoptotic pathway in THP1 cells. Differentiated human adipocytes did not show any significant increase in apoptosis after treatment in vitro with piolgitazone. These findings indicate that PPARgamma has distinct functions in different cell types in WAT, such that pioglitazone reduces macrophage infiltration by inducing apoptotic cell death specifically in macrophages through PPARgamma activation.

Adipocytes↗

PubMed2006

Effect of flywheel-based resistance exercise on processes contributing to muscle atrophy during unloading in adult rats.

Flywheel-based resistance exercise (RE) attenuates muscle atrophy during hindlimb suspension. We have previously shown that protein synthesis is elevated in response to RE, but the effect on protein degradation, cell proliferation, or apoptosis was not investigated. We hypothesized that, in addition to affecting protein synthesis, RE inhibits processes that actively contribute to muscle atrophy during hindlimb suspension. Male rats were housed in regular cages (control), tail suspended for 2 wk (HS), or HS with RE every other day for 2 wk (HSRE). Although RE attenuated soleus muscle atrophy during HS, the observed fivefold elevation in apoptosis and the 53% decrease in cell proliferation observed with HS were unaffected by RE. Expression of genes encoding components of the ubiquitin-proteasome pathway of protein degradation were elevated with HS, including ubiquitin, MAFbx, Murf-1, Nedd4, and XIAP, and proteasome subunits C2 and C9. Total ubiquitinated protein was increased with HS, but proteasome activity was not different from control. RE selectively altered the expression of different components of this pathway: MAFbx, Murf-1, and ubiquitin mRNA abundance were downregulated, whereas C2 and C9 subunits remained elevated. Similarly, Nedd4 and XIAP continued to be upregulated, potentially accounting for the observed augmentation in total ubiquitinated protein with RE. Thus a different constellation of proteins is likely ubiquitinated with RE due to altered ubiquitin ligase composition. In summary, the flywheel-based resistance exercise paradigm used in this study is associated with the inhibition of some mechanisms associated with muscle atrophy, such as the increase in MAFbx and Murf-1, but not with others, such as proteasome subunit remodeling, apoptosis, and decreased proliferation, potentially accounting for the inability to completely restore muscle mass. Identifying specific exercise parameters that affect these latter processes may be useful in designing effective exercise strategies in the elderly or during spaceflight.

Animals↗

PubMed2006

Aging alters macrophage properties in human skeletal muscle both at rest and in response to acute resistance exercise.

Macrophages are involved in skeletal muscle repair through pro-inflammatory and alternative functions. We tested the hypothesis that aging alters the abundance and properties of skeletal muscle macrophages that will influence their functional response to acute resistance exercise. Total macrophages (CD 68+), as well as pro- (CD 11b+) and anti-inflammatory (CD 163+) subpopulations and associated cytokine mRNAs were quantified in vastus lateralis biopsies from young (N=17) and elderly (N=17) males pre- and 72 h post-exercise. Pre-exercise, young muscle tended to possess a greater number of macrophages, whereas elderly muscle possessed higher levels of IL-1 beta (P=0.001), IL-1 RA (P=0.003), and IL-10 (P=0.028). Post-exercise, total macrophages did not change in either group, however, the number of CD 11b+ (P=0.039) and CD 163+ (P=0.026) cells increased 55 and 29%, respectively, but only in the young. IL-1 beta (P=0.006), IL-10 (P=0.016), and AMAC-1 (P=0.044) also increased, approximately two-fold, and again only in the young. Quantitation of CD 11b+ and CD 163+ cells suggests that the majority of resident macrophages possess alternative functions, and a small subpopulation participates in the inflammatory response. Both subpopulations increased their activity post-exercise, exclusively in the young. These findings suggest that aging results in a defective regulation of muscle macrophage function, both at baseline and in response to resistance exercise, that may limit muscle hypertrophy in older adults.

Adult↗

PubMed2006

Insulin-facilitated increase of muscle protein synthesis after resistance exercise involves a MAP kinase pathway.

Recent studies have implicated the mTOR-signaling pathway as a primary component for muscle growth in mammals. The purpose of this investigation was to examine signaling pathways for muscle protein synthesis after resistance exercise. Sprague-Dawley rats (male, 6 mo old) were assigned to either resistance exercise or control groups. Resistance exercise was accomplished in operantly conditioned animals using a specially designed flywheel apparatus. Rats performed two sessions of resistance exercise, separated by 48 h, each consisting of 2 sets of 25 repetitions. Sixteen hours after the second session, animals were killed, and soleus muscles were examined for rates of protein synthesis with and without insulin and/or rapamycin (mTOR inhibitor) and/or PD-098059 (PD; MEK kinase inhibitor). Results of this study demonstrated that rates of synthesis were higher (P < 0.05) with insulin after exercise compared with without insulin, or to control muscles, regardless of insulin. Rapamycin lowered (P < 0.05) rates of synthesis in controls, with or without insulin, and after exercise without insulin. However, insulin was able to overcome the inhibition of rapamycin after exercise (P < 0.05). PD had no effect on protein synthesis in control rats, but the addition of PD to exercised muscle resulted in lower (P < 0.05) rates of synthesis, and this inhibition was not rescued by insulin. Western blot analyses demonstrated that the inhibitors used in the present study were selective and effective for preventing activation of specific signaling proteins. Together, these results suggest that the insulin-facilitated increase of muscle protein synthesis after resistance exercise requires multiple signaling pathways.

Animals↗

PubMed2006

Assessing the reliability of amplified RNA used in microarrays: a DUMB table approach.

A certain minimal amount of RNA from biological samples is necessary to perform a microarray experiment with suitable replication. In some cases, the amount of RNA available is insufficient, necessitating RNA amplification prior to target synthesis. However, there is some uncertainty about the reliability of targets that have been generated from amplified RNA, because of nonlinearity and preferential amplification. This current work develops a straightforward strategy to assess the reliability of microarray data obtained from amplified RNA. The tabular method we developed, which utilises a Down-Up-Missing-Below (DUMB) classification scheme, shows that microarrays generated with amplified RNA targets are reliable within constraints. There was an increase in false negatives because of the need for increased filtering. Furthermore, this analysis method is generic and can be broadly applied to evaluate all microarray data. A copy of the Microsoft Excel spreadsheet is available upon request from Edward Bearden.

Benzothiazoles↗

PubMed2005

Cross-contamination of the PSP sensor in a preclinical setting.

PURPOSE: This study tested an infection control protocol for photostimulable phosphor (PSP) sensors while simulating multiple uses. METHODS: Dental hygiene students (n=36) were randomly assigned to a control group (dry wipe) or test group (disinfectant wipe). A sterile, barriered sensor was placed in a peer patient's mouth to simulate an exposure. After simulation, the barriered sensors were disinfected, placed into a new barrier, and inserted into the same peer patient's mouth. Following the fourth placement and treatment, sensors were vortexed in specimen cups containing trypticase soy broth (TSB) and incubated at 37 degrees C to detect contamination by oral bacteria. RESULTS: Bacterial growth in TSB was monitored as a change in optical density and by quantitation of oral streptococci on Mitis-salivarius agar. The barrier-protected sensors were minimally contaminated (<10(5) colony forming units/ml at baseline) regardless of treatment. After culture amplification, the control TSB had more samples that remained negative through 48 hours (5/18 vs. 0/18 for test group, p<0.05). CONCLUSION: Barrier envelopes used with the PSP sensors appeared to be an effective way of reducing microbial contamination.

Biphenyl Compounds↗

PubMed2005

Wnt10b deficiency promotes coexpression of myogenic and adipogenic programs in myoblasts.

Adult myoblasts retain plasticity in developmental potential and can be induced to undergo myogenic, adipogenic, or osteoblastogenic differentiation in vitro. In this report, we show that the balance between myogenic and adipogenic potential in myoblasts is controlled by Wnt signaling. Furthermore, this balance is altered during aging such that aspects of both differentiation programs are coexpressed in myoblasts due to decreased Wnt10b abundance. Mimicking Wnt signaling in aged myoblasts through inhibition of glycogen synthase kinase or through overexpression of Wnt10b resulted in inhibition of adipogenic gene expression and sustained or enhanced myogenic differentiation. On the other hand, myoblasts isolated from Wnt10b null mice showed increased adipogenic potential, likely contributing to excessive lipid accumulation in actively regenerating myofibers in vivo in Wnt10b-/- mice. Whereas Wnt10b deficiency contributed to increased adipogenic potential in myoblasts, the augmented myogenic differentiation potential observed is likely the result of a compensatory increase in Wnt7b during differentiation of Wnt10b-/- myoblasts. No such compensation was apparent in aged myoblasts and in fact, both Wnt5b and Wnt10b were down-regulated. Thus, alteration in Wnt signaling in myoblasts with age may contribute to impaired muscle regenerative capacity and to increased muscle adiposity, both characteristic of aged muscle.

Adipocytes↗

PubMed2005

Upstream CpG island methylation of the PAX3 gene in human rhabdomyosarcomas.

BACKGROUND: Adult tumors can be characterized by hypermethylation of CpG islands associated with 5'-upstream and coding regions of specific genes. This hypermethylation can also be part of the aging process. In contrast, much less is known about gene hypermethylation in childhood cancers, where methylation changes are not part of the aging process but likely represent developmental dysregulation. PAX3 is an important gene in muscle development and muscle-producing neoplasms such as rhabdomyosarcomas. PROCEDURES: We examined the methylation status of a PAX3 5'-CpG island in rhabdomyosarcoma subtypes and in normal fetal skeletal muscle. PAX3 methylation was analyzed in 15 embryonal rhabdomyosarcomas, 12 alveolar rhabdomyosarcomas, and in six normal skeletal muscle samples, using semi-quantitative PCR analysis of DNA digested with methyl-sensitive restriction enzymes. RESULTS: The CpG island in the upstream region of the human PAX3 gene was hypermethylated in the majority of ERMS examined (13 of 15 tumors, mean of 52% methylation), whereas most ARMS (9 of 12 tumors) and all normal muscle samples showed relative hypomethylation (both 18% mean methylation). Various CpG sites differ in contribution to overall PAX3 CpG island methylation, with methylation at a HaeII site being inversely correlated with PAX3 expression. CONCLUSIONS: PAX3 CpG island methylation appears to distinguish embryonal subtype of rhabdomyosarcoma from alveolar, and methylation at certain sites within this CpG island is inversely correlated with PAX3 expression. In addition to exemplifying developmental dysregulation, methylation of PAX3 has potential in the development of an epigenetic profile for the diagnosis of rhabdomyosarcoma.

Child↗

PubMed2005

Expression of CD68 and macrophage chemoattractant protein-1 genes in human adipose and muscle tissues: association with cytokine expression, insulin resistance, and reduction by pioglitazone.

To examine the role of adipose-resident macrophages in insulin resistance, we examined the gene expression of CD68, a macrophage marker, along with macrophage chemoattractant protein-1 (MCP-1) in human subcutaneous adipose tissue using real-time RT-PCR. Both CD68 and MCP-1 mRNAs were expressed in human adipose tissue, primarily in the stromal vascular fraction. When measured in the adipose tissue from subjects with normal glucose tolerance, covering a wide range of BMI (21-51 kg/m2) and insulin sensitivity (S(I)) (0.6-8.0 x 10(-4)min(-1).microU(-1).ml(-1)), CD68 mRNA abundance, which correlated with the number of CD68-positive cells by immunohistochemistry, tended to increase with BMI but was not statistically significant. However, there was a significant inverse relation between CD68 mRNA and S(I) (r=-0.55, P=0.02). In addition, there was a strong positive relationship among adipose tissue CD68 mRNA, tumor necrosis factor-alpha (TNF-alpha) secretion in vitro (r=0.79, P<0.005), and plasma interleukin-6 (r=0.67, P < 0.005). To determine whether improving S(I) in subjects with impaired glucose tolerance (IGT) was associated with decreased CD68 expression, IGT subjects were treated for 10 weeks with pioglitazone or metformin. Pioglitazone increased S(I) by 60% and in the same subjects reduced both CD68 and MCP-1 mRNAs by >50%. Furthermore, pioglitazone resulted in a reduction in the number of CD68-positive cells in adipose tissue and reduced plasma TNF-alpha. Metformin had no effect on any of these measures. Thus, treatment with pioglitazone reduces expression of CD68 and MCP-1 in adipose tissue, apparently by reducing macrophage numbers, resulting in reduced inflammatory cytokine production and improvement in S(I).

Adipose Tissue↗

PubMed2004

Modeling genetic networks from clonal analysis.

In this report a systematic approach is used to determine the approximate genetic network and robust dependencies underlying differentiation. The data considered is in the form of a binary matrix and represent the expression of the nine genes across the 99 colonies. The report is divided into two parts: the first part identifies significant pair-wise dependencies from the given binary matrix using linear correlation and mutual information. A new method is proposed to determine statistically significant dependencies estimated using the mutual information measure. In the second, a Bayesian approach is used to obtain an approximate description (equivalence class) of network structures. The robustness of linear correlation, mutual information and the equivalence class of networks is investigated with perturbation and decreasing colony number. Perturbation of the data was achieved by generating bootstrap realizations. The results are refined with biological knowledge. It was found that certain dependencies in the network are immune to perturbation and decreasing colony number and may represent robust features, inherent in the differentiation program of osteoblast progenitor cells. The methods to be discussed are generic in nature and not restricted to the experimental paradigm addressed in this study.

Animals↗

PubMed2004

Interleukin-1 polymorphisms are associated with the inflammatory response in human muscle to acute resistance exercise.

Inflammation appears to play an important role in the repair and regeneration of skeletal muscle after damage. We tested the hypothesis that the severity of the inflammatory response in muscle after an acute bout of resistance exercise is associated with single nucleotide polymorphisms (SNPs) previously shown to alter interleukin-1 (IL-1) activity. Using a double-blind prospective design, sedentary young men were screened (n = 100) for enrolment (n = 24) based upon having 1 of 4 haplotype patterns composed of five polymorphic sites in the IL-1 gene cluster: IL-1A (+4845), IL-1B (+3954), IL-1B (-511), IL-1B (-3737) and IL-1RN (+2018). Subjects performed a standard bout of resistance leg exercise and vastus lateralis biopsies were obtained pre-, and at 24, and 72 h post-exercise. Inflammatory marker mRNAs (IL-1beta, IL-6 and tumor necrosis factor-alpha (TNF-alpha)) and the number of CD68(+) macrophages were quantified. Considerable variation was observed in the expression of these gene products between subjects. At 72 h post-exercise, IL-1beta had increased in a number of subjects (n = 10) and decreased (n = 4) or did not change (n = 10) in others. Inflammatory responses were significantly associated with specific haplotype patterns and were also influenced by individual SNPs. Subjects with genotypes 1.1 at IL-1B (+3954) or 2.2 at IL-1B (-3737) had approximately a 2-fold higher median induction of several markers, but no increase in macrophages, suggesting that cytokine gene expression is elevated per macrophage. The IL-1RN (+2018) SNP maximized the response specifically within these groups and was associated with increased macrophage recruitment. This is the first report that IL-1 genotype is associated with the inflammation of skeletal muscle following acute resistance exercise that may potentially affect the adaptations to chronic resistance exercise.

Adult↗

PubMed2004

Insulin facilitation of muscle protein synthesis following resistance exercise in hindlimb-suspended rats is independent of a rapamycin-sensitive pathway.

Hindlimb suspension (HS) results in rapid losses of muscle mass, which may in part be explained by attenuated rates of protein synthesis. Mammalian target of rapamycin (mTOR) regulates protein synthesis and has been implicated as a potential mediator of the muscle mass decrement with HS. This study examined the effect of resistance exercise, a muscle hypertrophy stimulant, on rates of protein synthesis after 4 days of HS in mature male Sprague-Dawley rats. Flywheel resistance exercise (2 sets x 25 repetitions) was conducted on days 2 and 4 of HS (HSRE). Sixteen hours after the last exercise bout, soleus muscles were assessed for in vitro rates of protein synthesis, with and without insulin (signaling agonist) and/or rapamycin (mTOR inhibitor). Results demonstrated that soleus mass was reduced (P < 0.05) with HS, but this loss of mass was not observed (P > 0.05) with HSRE. Muscle protein synthesis was diminished (P < 0.05) with HS, with or without insulin. HSRE also had reduced rates of synthesis without insulin; however, insulin administration yielded higher (P < 0.05) rates in HSRE compared with HS or control. Rapamycin diminished protein synthesis in all groups (P < 0.05), but insulin rescued synthesis rates in HS and HSRE to levels similar to insulin alone for each group, suggesting that alternate signaling pathways develop to increase protein synthesis with HS. These results demonstrate that the capacity for an augmented anabolic response to resistance exercise is maintained after 4 days of HS and is independent of a rapamycin-sensitive pathway.

Animals↗

PubMed2004

Changes in expression level of genes as a function of time of day in the liver of rats.

Daily, rhythmic variation in various biochemical, physiological, and behavioral events is a fundamental property of biological organization. Here, we report analysis of relative levels of gene expression in the liver of 16 Fischer 344 rats as a function of time of day. Expression levels were determined for 3906 genes using high-density oligonucleotide microarrays. Of the 3906 genes, 1171 (30%) were clearly expressed while 2735 (70%) were not expressed or the expression was too low to distinguish from background levels. The maximum estimated changes observed for most genes (1029, 88%) were less than 1.5-fold. Analysis of variance and the Kruskal-Wallis tests were used to identify 67 genes whose expression was significantly altered as a function of time of day. These significantly altered genes were classified according to their functions and fall into key cellular pathways including drug metabolism, ion transport, signal transduction, DNA binding and regulation of transcription, and immune response.

Animals↗

PubMed2004

Satellite cell regulation of muscle mass is altered at old age.

Muscle mass is decreased with advancing age, likely due to altered regulation of muscle fiber size. This study was designed to investigate cellular mechanisms contributing to this process. Analysis of male Fischer 344 X Brown Norway rats at 6, 20, and 32 mo of age demonstrated that, even though significant atrophy had occurred in soleus muscle by old age, myofiber nuclear number did not change, resulting in a decreased myonuclear domain. Also, the number of centrally located nuclei was significantly elevated in soleus muscle of 32-mo-old rats, correlating with an increase in gene expression of MyoD and myogenin. Whereas total 5'-bromo-2'deoxyuridine (BrdU)-positive nuclei were decreased at older ages, BrdU-positive myofiber nuclei were increased. These results suggest that, with age, loss of muscle mass is accompanied by increased myofiber nuclear density that involves fusion of proliferative satellite cells, resembling ongoing regeneration. Interestingly, centrally located myofiber nuclei were not BrdU labeled. Rats were subjected to hindlimb suspension (HS) for 7 or 14 days and intermittent reloading during HS for 1 h each day (IR) to investigate how aging affects the response of soleus muscle to disuse and an atrophy-reducing intervention. After 14 days of HS, soleus muscle size was decreased to a similar extent at all three ages. However, myofiber nuclear number and the total number of BrdU-positive nuclei decreased with HS only in the young rats. IR was associated with an attenuation of atrophy in soleus muscles of 6- and 20- but not 32-mo-old rats. Furthermore, IR was associated with an increase in BrdU-positive myofiber nuclei only in young rats. These data indicate that altered satellite cell function with age contributes to the impaired response of soleus muscle to an intervention that attenuates muscle atrophy in young animals during imposed disuse.

Adaptation, Physiological↗

PubMed2004

Microarray analysis of differentiation-specific gene expression during 3T3-L1 adipogenesis.

During cellular differentiation and development, it is recognized that many complex molecular mechanisms as well as precise patterns of differentially expressed genes occur in directing precursor cells toward a given lineage. Using microarray-based technology, we examined gene expression across the course of 3T3-L1 adipocyte differentiation. Total cellular RNA was isolated at times 0, 2, 8, 16, 24, 48, and 96 h following treatment with either standard hormonal inducers of differentiation; insulin, dexamethasone, isobutylmethylxanthine (IDX), or IDX plus trichostatin A (TsA), a histone deacetylase inhibitor and potent adipogenic inhibitor. cRNA was synthesized from cellular RNA and hybridized to high density Affymetrix MG_U74Av2 microarray gene chips containing 12,488 cDNA/Expressed Sequence Tags (ESTs) probe sets. From the IDX-only treated cells, all probe sets that were either unchanged or differentially expressed less than 2-fold throughout differentiation with respect to time 0 preadipocytes were excluded from further analyses. This selection resulted in a net of 1686 transcripts, 859 were increased in expression, and 827 were decreased in expression at least 2-fold across differentiation. To focus in on genes that were more specific to differentiation, the same analysis was performed on IDX plus TsA-treated non-differentiating cells and all probe sets from the IDX-only group that exhibited similar expression profiles in the non-differentiating TsA-treated group were excluded leaving a total of 1016 transcripts that were regulated only under differentiating conditions. Six hundred and thirty-six of these transcripts were elevated at least 2-fold and 380 exhibited a decrease in expression relative to time 0 preadipocytes. This group of genes was further analyzed using hierarchical clustering and self-organizing maps and resulted in the identification of numerous genes not previously known to be regulated during adipocyte differentiation. Many of these genes may well represent novel adipogenic mediators and markers of adipogenesis.

1-Methyl-3-isobutylxanthine↗

PubMed2004

Exercise-induced gene expression in soleus muscle is dependent on time after spinal cord injury in rats.

Cycling exercise attenuates atrophy in hindlimb muscles and causes changes in spinal cord properties after spinal cord injury in rats. We hypothesized that exercising soleus muscle expresses genes that are potentially beneficial to the injured spinal cord. Rats underwent spinal cord injury at T10 and were exercised on a motor-driven bicycle. Soleus muscle and lumbar spinal cord tissue were used for messenger RNA (mRNA) analysis. Gene expression of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) was elevated 11- and 14-fold, respectively, in soleus muscle after one bout of exercise performed 5 days after spinal cord transection. Also, c-fos and heat shock protein-27 (HSP27) mRNA abundance were increased 11- and 7-fold, respectively. When exercise was started 2 days after the injury, the changes in gene expression were not observed. By contrast, at 2 but not at 5 days after transection, expression of the HSP27 gene was elevated sixfold in the lumbar spinal cord, independent of exercise. Electromyographic activity in soleus muscles was also decreased at 2 days, indicating that the spinal cord was less permissive to exercise at this early time. Long-term exercise for 4 weeks attenuated muscle atrophy equally well in rats started at 2 days or 5 days after injury. We conclude that BDNF and GDNF released from exercising muscle may be involved in exercise-induced plasticity of the spinal cord. Furthermore, the data suggest that the lumbar spinal cord undergoes time-dependent changes that temporarily impede the ability of the muscle to respond to exercise.

Action Potentials↗

PubMed2004

Passive exercise and fetal spinal cord transplant both help to restore motoneuronal properties after spinal cord transection in rats.

Spinal cord transection influences the properties of motoneurons and muscles below the lesion, but the effects of interventions that conserve muscle mass of the paralyzed limbs on these motoneuronal changes are unknown. We examined the electrophysiological properties of rat lumbar motoneurons following spinal cord transection, and the effects of two interventions shown previously to significantly attenuate the associated hindlimb muscle atrophy. Adult rats receiving a complete thoracic spinal cord transection (T-10) were divided into three groups receiving: (1) no further treatment; (2) passive cycling exercise for 5 days/week; or (3) acute transplantation of fetal spinal cord tissue. Intracellular recording of motoneurons was carried out 4-5 weeks following transection. Transection led to a significant change in the rhythmic firing patterns of motoneurons in response to injected currents, as well as a decrease in the resting membrane potential and spike trigger level. Transplants of fetal tissue and cycling exercise each attenuated these changes, the latter having a stronger effect on maintenance of motoneuron properties, coinciding with the reported maintenance of structural and biochemical features of hindlimb muscles. The mechanisms by which these distinct treatments affect motoneuron properties remain to be uncovered, but these changes in motoneuron excitability are consistent with influences on ion conductances at or near the initial segment. The results may support a therapeutic role for passive limb manipulation and transplant of stem cells in slowing the deleterious responses of motoneurons to spinal cord injury, such that they remain more viable for subsequent alternative strategies.

Animals↗