C174T polymorphism in the CNTF receptor gene is associated with fat-free mass in men and women.

We performed gene screening of the ciliary neurotrophic factor receptor (CNTFR) gene and genotyped three newly identified polymorphisms: C-1703T in the 5' promoter region, T1069A in intron 5, and C174T in exon 9. We studied the association of these CNTFR variants with muscle strength, mass, and body composition in 465 men and women (20-90 yr) from the Baltimore Longitudinal Study of Aging. Only the C174T variant was significantly associated with muscle-related phenotypes. In the entire cohort, when corrected for age, sex, race, physical activity, and height, homozygotes for the common C allele at C174T (CC) exhibited lower total body mass and body mass index than carriers of the rare T allele, which appeared to be due to significant differences in total nonosseous fat-free mass (FFM) (48.0 +/- 0.4 vs. 50.0 +/- 0.7 kg; P = 0.011) and lower limb FFM (16.5 +/- 0.1 vs. 17.2 +/- 0.2 kg; P = 0.002). The CC group also exhibited significantly lower quadriceps concentric and eccentric isokinetic strength values at both 30 and 180 degrees /s than the T allele carriers (all P < 0.04), but these differences were no longer significant after adjustment for lower limb FFM. There were no significant sex-by-genotype interactions. The results indicate that the C174T polymorphism in exon 9 of CNTFR is significantly associated with FFM in men and women, with concomitant differences in muscular strength.     

CNTF genotype is associated with muscular strength and quality in humans across the adult age span.

The relationship between ciliary neurotrophic factor (CNTF) genotype and muscle strength was examined in 494 healthy men and women across the entire adult age span (20-90 yr). Concentric (Con) and eccentric (Ecc) peak torque were assessed using a Kin-Com isokinetic dynamometer for the knee extensors (KE) and knee flexors (KF) at slow (0.52 rad/s) and faster (3.14 rad/s) velocities. The results were covaried for age, gender, and body mass or fat-free mass (FFM). Individuals heterozygous for the CNTF null (A allele) mutation (G/A) exhibited significantly higher Con peak torque of the KE and KF at 3.14 rad/s than G/G homozygotes when age, gender, and body mass were covaried (P < 0.05). When the dominant leg FFM (estimated muscle mass) was used in place of body mass as a covariate, Con peak torque of the KE at 3.14 rad/s was also significantly greater in the G/A individuals (P < 0.05). In addition, muscle quality of the KE (peak torque at 3.14 rad x s(-1) x leg muscle mass(-1)) was significantly greater in the G/A heterozygotes (P < 0.05). Similar results were seen in a subanalysis of subjects 60 yr and older, as well as in Caucasian subjects. In contrast, A/A homozygotes demonstrated significantly lower Ecc peak torque at 0.52 rad/s for both KE and KF compared with G/G and G/A groups (P < 0.05). No significant relationships were observed at 0.52 rad/s between genotype and Con peak torque. These data indicate that individuals exhibiting the G/A genotype possess significantly greater muscular strength and muscle quality at relatively fast contraction speeds than do G/G individuals. Because of high positive correlations between fast-velocity peak torque and muscular power, these findings suggest that further investigations should address the relationship between CNTF genotype and muscular power.     

Age-related fatigability in knee extensors and knee flexors during dynamic fatiguing contractions

This study investigated the effects of dynamic knee extension and flexion fatiguing task on torque and neuromuscular responses in young and older individuals. Eighteen young (8 males; 25.1 ± 3.2 years) and 17 older (8 males; 69.7 ± 3.7 years) volunteered. Following a maximal voluntary isometric contraction test, participants performed a fatiguing task involving 22 maximal isokinetic (concentric) knee extension and flexion contractions at 60°/s, while surface EMG was recorded simultaneously from the knee extensors (KE) and flexors (KF). Fatigue-induced relative torque reductions were similar between age groups for KE (peak torque decrease: 25.15% vs 26.81%); however, KF torque was less affected in older individuals (young vs older peak torque decrease: 27.6% vs 11.5%; p < 0.001) and this was associated with greater increase in hamstring EMG amplitude (p < 0.001) and hamstrings/quadriceps peak torque ratio (p < 0.01). Furthermore, KE was more fatigable than KF only among older individuals (peak torque decrease: 26.8% vs 11.5%; p < 0.001). These findings showed that the age-related fatigue induced by a dynamic task was greater for the KE, with greater age-related decline in KE compared to KF.     

Solution structure of the C-terminal domain of the ciliary neurotrophic factor (CNTF) receptor and ligand free associations among components of the CNTF receptor complex

The functional receptor complex of ciliary neurotrophic factor (CNTF), a member of the gp130 family of cytokines, is composed of CNTF, the CNTF receptor alpha (CNTFR), gp130, and the leukemia inhibitory factor receptor (LIFR). However, the nature of the receptor-mediated interactions in this complex has not yet been resolved. To address this issue we have determined the solution structure of the C-terminal or BC domain of CNTFR and studied the interactions of CNTFR with LIFR and gp130. We reported previously that the membrane distal cytokine-binding domain (CBD1) of LIFR could interact in vitro with soluble CNTFR (sCNTFR) in the absence of CNTF. Here we show that the CBD of human gp130 can also bind in vitro to sCNTFR in the absence of CNTF. In addition, the gp130 CBD could compete with the LIFR CBD1 for the binding of sCNTFR. Substitution of residues in the gp130 CBD, the LIFR CBD1, and the CNTFR BC domain that are expected to be involved in receptor-receptor interactions significantly reduced their interactions. An NMR chemical shift perturbation study of the interaction between the BC domains of CNTFR and gp130 further mapped the interaction surface. These data suggest that both the gp130 CBD and the LIFR CBD1 interact with CNTFR in a similar way and provide insights into the nature of the CNTF receptor complex.     

Eccentric and concentric torque-velocity characteristics of the quadriceps femoris in man

The primary purpose of this investigation was to study the eccentric and concentric torque-velocity characteristics of the quadriceps femoris in man using a recently developed combined isometric, concentric and eccentric controlled velocity dynamometer (the SPARK System). A secondary purpose was to compare the method error associated with maximal voluntary concentric and eccentric torque output over a range of testing velocities. 21 males (21-32 years) performed on two separate days maximal voluntary isometric, concentric and eccentric contractions of the quadriceps femoris at 4 isokinetic lever arm velocities of 0 degree.s-1 (isometric), 30 degrees.s-1, 120 degrees.s-1 and 270 degrees.s-1. Eccentric peak torque and angle-specific torques (measured every 10 degrees from 30 degrees to 70 degrees) did not significantly change from 0 degrees.s-1 to 270 degrees.s-1 (p greater than 0.005) with the exception of angle-specific 40 degrees torque, which significantly increased; p less than 0.05). The mean method error was significantly higher for the eccentric tests (10.6% +/- 1.6%) than for the concentric tests (8.1% +/- 1.7%) (p less than 0.05). The mean method error decreased slightly with increasing concentric velocity (p greater than 0.05), and increased slightly with increasing eccentric velocity (p greater than 0.05). A tension restricting neural mechanism, if active during maximal eccentric contractions, could possibly account for the large difference seen between the present eccentric torque-velocity results and the classic results obtained from isolated animal muscle.     

Changes in expression of ciliary neurotrophic factor (CNTF) and CNTF-receptor α after spinal cord injury

To determine if ciliary neurotrophic factor (CNTF) is involved in the response to spinal cord injury, we studied changes in the expression of CNTF and that of its receptor, CNTF-receptor α (CNTFRα), in the rat spinal cord after a unilateral spinal cord hemisection. Using in situ hybridization, we found that CNTFRα mRNA levels in spinal cord motoneurons increased dramatically by 1 day after hemisecting the spinal cord at T2. This increase in expression was present only in motoneurons caudal, but not rostral, to the lesion. In addition, we detected increased levels of CNTF mRNA in the spinal cord white matter, also by 1 day following injury. Unlike CNTFRα, however, the increase in CNTF mRNA was evident both rostral and caudal to the lesion. Levels of both CNTF and CNTFRα mRNA declined between 1 and 5 days, and by 10 days they were not significantly different from normal animals. These findings suggest that CNTF may play a local role in the response to spinal cord injury. © 1997 John Wiley & Sons, Inc. J Neurobiol 32: 251–261, 1997.     

CNTF variants with increased biological potency and receptor selectivity define a functional site of receptor interaction.

Human CNTF is a neurocytokine that elicits potent neurotrophic effects by activating a receptor complex composed of the ligand-specific alpha-receptor subunit (CNTFR alpha) and two signal transducing proteins, which together constitute a receptor for leukemia inhibitory factor (LIFR). At high concentrations, CNTF can also activate the LIFR and possibly other cross-reactive cytokine receptors in the absence of CNTFR alpha. To gain a better understanding of its structure-function relationships and to develop analogs with increased receptor specificity, the cytokine was submitted to affinity maturation using phage display technology. Variants with greatly increased CNTFR alpha affinity were selected from a phage-displayed library of CNTF variants carrying random amino acid substitutions in the putative D helix. Selected variants contained substitutions of the wild-type Gln167 residue, either alone or in combination with neighboring mutations. These results provide evidence for an important functional role of the mutagenized region in CNTFR alpha binding. Affinity enhancing mutations conferred to CNTF increased potency to trigger biological effects mediated by CNTFR alpha and enhanced neurotrophic activity on chicken ciliary neurons. In contrast, the same mutations did not potentiate the CNTFR alpha-independent receptor actions of CNTF. These CNTF analogs thus represent receptor-specific superagonists, which should help to elucidate the mechanisms underlying the pleiotropic actions of the neurocytokine.     

Detection of ligand-induced CNTF receptor dimers in living cells by fluorescence cross correlation spectroscopy

Ciliary neurotrophic factor (CNTF) signals via a receptor complex consisting of the specific CNTF receptor (CNTFR) and two promiscuous signal transducers, gp130 and leukemia inhibitory factor receptor (LIFR). Whereas earlier studies suggested that the signaling complex is a hexamer, more recent analyses strongly support a tetrameric structure. However, all studies so far analyzed the stoichiometry of the CNTF receptor complex in vitro and not in the context of living cells. We generated and expressed in mammalian cells acyl carrier protein-tagged versions of both CNTF and CNTFR. After labeling CNTF and CNTFR with different dyes we analyzed their diffusion behavior at the cell surface. Fluorescence (cross) correlation spectroscopy (FCS/FCCS) measurements reveal that CNTFR diffuses with a diffusion constant of about 2 × 10^− 9 cm² s^− 1 independent of whether CNTF is bound or not. FCS and FCCS measurements detect the formation of receptor complexes containing at least two CNTFs and CNTFRs. In addition, we measured Förster-type fluorescence resonance energy transfer between two differently labeled CNTFs within a receptor complex indicating a distance of 5-7 nm between the two. These findings are not consistent with a tetrameric structure of the CNTFR complex suggesting that either hexamers and or even higher-order structures (e.g. an octamer containing two tetramers) are formed.     

Muscle architecture and force-velocity relationships in humans

The in vivo torque-velocity relationships of the knee extensors (KE), knee flexors (KF), ankle plantarflexors (PF), and ankle dorsiflexors (DF) were determined in 12 untrained subjects using an isokinetic testing device (Cybex II). These data were then matched to the predicted maximum forces and shortening velocities derived from muscle architectural determinations made on three hemipelvectomies (36). The torque-velocity curves of all muscle groups resembled that predicted by Hill's (19, 20) equation except at the higher forces and lower velocities. The peak torques occurred at mean velocities ranging from 41-62 rad X s-1 for the KE, KF, and PF. Although the peak torque of the DF occurred at the isometric loading condition, it was also lower than that predicted by Hill's equation. The muscle fiber length and physiological cross-sectional area measurements indicate that the architecture of the human leg musculature has a major influence on the torque-velocity characteristics. These data corroborate previous findings (24) that some neural inhibitory mechanism exists in the control of the leg musculature, which limits the maximum forces that could be produced under optimal stimulating conditions.     

Expression of biologically active mouse ciliary neutrophic factor (CNTF) and soluble CNTFRalpha in Escherichia coli and characterization of their functional specificities

Ciliary neurotrophic factor (CNTF) is a neuroprotective cytokine initially identified in chick embryo. It has been evaluated for the treatment of neurodegenerative diseases. CNTF also acts on non-neuronal cells such as oligodendrocytes, astrocytes, adipocytes and skeletal muscles cells. CNTF has regulatory effects on body weight and is currently in clinical trial for the treatment of diabetes and obesity. CNTF mediates its function by activating a tripartite receptor comprising the CNTF receptor alpha chain (CNTFRalpha), the leukemia inhibitory factor receptor beta chain (LIFRbeta) and gp130. Human, rat and chicken CNTF have been expressed as recombinant proteins, and most preclinical studies in murine models have been performed using rat recombinant protein. Rat and human CNTF differ in their fine specificities: in addition to CNTFR, rat CNTF has been shown to activate the LIFR (a heterodimer of LIFRbeta and gp130), whereas human CNTF can bind and activate a tripartite receptor comprising the IL-6 receptor alpha chain (IL-6Ralpha) and LIFR. To generate tools designed for mouse models of human diseases; we cloned and expressed in E. coli both mouse CNTF and the CNTFRalpha chain. Recombinant mouse CNTF was active and showed a high level of specificity for mouse CNTFR. It shares the arginine residue with rat CNTF which prevents binding to IL-6Ralpha. It did not activate the LIFR at all concentrations tested. Recombinant mouse CNTF is therefore specific for CNTFR and as such represents a useful tool with which to study CNTF in mouse models. It appears well suited for the comparative evaluation of CNTF and the two additional recently discovered CNTFR ligands, cardiotrophin-like cytokine\cytokine-like factor-1 and neuropoietin.     

Influence of the intensity of a conditioning contraction on the subsequent twitch torque and maximal voluntary concentric torque

This study aimed to clarify the influence of the intensity of a conditioning contraction on subsequent isometric twitch and maximal voluntary concentric torques. Subjects (n=12men) performed voluntary isometric plantar flexion for six seconds as a conditioning contraction, at intensities of 40%, 60%, 80% and 100% of a maximal voluntary isometric contraction (MVIC). Before and immediately after the conditioning contraction, isometric twitch and maximal voluntary concentric (180°/s) plantar flexion torques were determined. Surface electromyograms were recorded from the triceps surae muscles and M-wave amplitudes and root-mean-square values of the electromyographic signals (RMS(EMG)) were calculated. The isometric twitch torque increased significantly after conditioning contraction at all intensities (P<0.05), whereas maximal voluntary concentric torque increased significantly only at 80% and 100% MVIC conditions (P<0.05). It is concluded that during a six second conditioning contraction, the effect of the intensity of a conditioning contraction on subsequent torque development is different between an isometric twitch and maximal voluntary concentric contractions, with the latter being less affected.     

Gene expression of receptors for IL-6, LIF, and CNTF in regenerating skeletal muscles.

The biological actions of interleukin-6 (IL-6), leukemia inhibitory factor (LIF), and ciliary neurotrophic factor (CNTF) are mediated via respective functional receptor complexes consisting of a common signal-transducing component, gp130, and other specific receptor components, IL-6 receptor alpha (IL-6R), LIF receptor beta (LIFR), and CNTF receptor alpha (CNTFR). IL-6, LIF, and CNTF are implicated in skeletal muscle regeneration. However, the cell populations that express these receptor components in regenerating muscles are unknown. Using in situ hybridization histochemistry, we examined spatiotemporal expression patterns of gp130, IL-6R, LIFR, and CNTFR mRNAs in regenerating muscles after muscle contusion. At the early stages of regeneration (from 3 hr to Day 2 post contusion), significant signals for gp130 and LIFR mRNAs were detected in myonuclei and/or nuclei of muscle precursor cells (mpcs) and in mononuclear cells located in extracellular spaces between myofibers after muscle contusion, but IL-6R mRNA was expressed only in mononuclear cells. At Day 7 post contusion, signals for gp130, LIFR, and IL-6R mRNAs were not detected in newly formed myotubes, whereas the CNTFR mRNA level was upregulated in myotubes. These findings suggest that the upregulation of receptor subunits in distinct cell populations plays an important role in the effective regeneration of both myofibers and motor neurons. (J Histochem Cytochem 48:1203-1213, 2000)     

The Amino Acid Exchange R28E in Ciliary Neurotrophic Factor (CNTF) Abrogates Interleukin-6 Receptor-dependent but Retains CNTF Receptor-dependent Signaling via Glycoprotein 130 (gp130)/Leukemia Inhibitory Factor Receptor (LIFR)

Ciliary neurotrophic factor (CNTF) is a neurotrophic factor with therapeutic potential for neurodegenerative diseases. Moreover, therapeutic application of CNTF reduced body weight in mice and humans. CNTF binds to high or low affinity receptor complexes consisting of CNTFR·gp130·LIFR or IL-6R·gp130·LIFR, respectively. Clinical studies of the CNTF derivative Axokine revealed intolerance at higher concentrations, which may rely on the low-affinity binding of CNTF to the IL-6R. Here, we aimed to generate a CNTFR-selective CNTF variant (CV). CV-1 contained the single amino acid exchange R28E. Arg²⁸ is in close proximity to the CNTFR binding site. Using molecular modeling, we hypothesized that Arg²⁸ might contribute to IL-6R/CNTFR plasticity of CNTF. CV-2 to CV-5 were generated by transferring parts of the CNTFR-binding site from cardiotrophin-like cytokine to CNTF. Cardiotrophin-like cytokine selectively signals via the CNTFR·gp130·LIFR complex, albeit with a much lower affinity compared with CNTF. As shown by immunoprecipitation, all CNTF variants retained the ability to bind to CNTFR. CV-1, CV-2, and CV-5, however, lost the ability to bind to IL-6R. Although all variants induced cytokine-dependent cellular proliferation and STAT3 phosphorylation via CNTFR·gp130·LIFR, only CV-3 induced STAT3 phosphorylation via IL-6R·gp130·LIFR. Quantification of CNTF-dependent proliferation of CNTFR·gp130·LIFR expressing cells indicated that only CV-1 was as biologically active as CNTF. Thus, the CNTFR-selective CV-1 will allow discriminating between CNTFR- and IL-6R-mediated effects in vivo.     

CNTF mediates neurotrophic factor secretion and fluid absorption in human retinal pigment epithelium

Ciliary neurotrophic factor (CNTF) protects photoreceptors and regulates their phototransduction machinery, but little is known about CNTF's effects on retinal pigment epithelial (RPE) physiology. Therefore, we determined the expression and localization of CNTF receptors and the physiological consequence of their activation in primary cultures of human fetal RPE (hfRPE). Cultured hfRPE express CNTF, CT1, and OsM and their receptors, including CNTFRα, LIFRβ, gp130, and OsMRβ, all localized mainly at the apical membrane. Exogenous CNTF, CT1, or OsM induces STAT3 phosphorylation, and OsM also induces the phosphorylation of ERK1/2 (p44/42 MAP kinase). CNTF increases RPE survivability, but not rates of phagocytosis. CNTF increases secretion of NT3 to the apical bath and decreases that of VEGF, IL8, and TGFβ2. It also significantly increases fluid absorption (J(V)) across intact monolayers of hfRPE by activating CFTR chloride channels at the basolateral membrane. CNTF induces profound changes in RPE cell biology, biochemistry, and physiology, including the increase in cell survival, polarized secretion of cytokines/neurotrophic factors, and the increase in steady-state fluid absorption mediated by JAK/STAT3 signaling. In vivo, these changes, taken together, could serve to regulate the microenvironment around the distal retinal/RPE/Bruch's membrane complex and provide protection against neurodegenerative disease.     

A new dynamometer measuring concentric and eccentric muscle strength in accelerated, decelerated, or isokinetic movements. Validity and reproducibility

A new computerized dynamometer (the SPARK System) is described. The system can measure concentric and eccentric muscle strength (torque) during linear or nonlinear acceleration or deceleration, isokinetic movements up to 400 degrees.s-1, and isometric torque. Studies were performed to assess: I. validity and reproducibility of torque measurements; II. control of lever arm position; III. control of different velocity patterns; IV. control of velocity during subject testing; and, V. intra-individual reproducibility. No significant difference was found between torque values computed by the system and known torque values (p greater than 0.05). No difference was present between programmed and external measurement of the lever arm position. Accelerating, decelerating and isokinetic velocity patterns were highly reproducible, with differences in elapsed time among 10 trials being never greater than 0.001 s. Velocity during concentric and eccentric isokinetic quadriceps contractions at 30 degrees.s-1, 120 degrees.s-1 and 270 degrees.s-1 never varied by more than 3 degrees.s-1 among subjects (N = 21). Over three days of testing, the overall error for concentric and eccentric quadriceps contraction peak torque values for 5 angular velocities between 30 degrees.s-1 and 270 degrees.s-1 ranged from 5.8% to 9.0% and 5.8% to 9.6% respectively (N = 25). The results indicate that the SPARK System provides valid and reproducible torque measurements and strict control of velocity. In addition, the intra-individual error is in accordance with those reported for other similar devices.     

Contractile and elastic ankle joint muscular properties in young and older adults

The purpose of this study was to investigate age-related differences in contractile and elastic properties of both dorsi- (DF) and plantarflexor (PF) muscles controlling the ankle joint in young and older adults. Experimental data were collected while twelve young and twelve older male and female participants performed maximal effort isometric and isovelocity contractions on a dynamometer. Equations were fit to the data to give torque-angle (Tθ) and torque-angular velocity (Tω) relations. Muscle series-elasticity was measured during ramped dynamometer contractions using ultrasonography to measure aponeurosis extension as a function of torque; second order polynomials were used to characterize the torque-extension (TΔL) relation. The results showed no age differences in DF maximal torque and none for female PF; however, older males had smaller maximal PF torques compared to young males. In both muscle groups and genders, older adults had decreased concentric force capabilities. Both DF and PF TΔL relations were more nonlinear in the older adults. Older PF, but not DF muscles, were stiffer compared to young. A simple antagonism model suggested age-related differences in Tθ and Tω relations would be magnified if antagonistic torque contributions were included. This assessment of static, dynamic, and elastic joint properties affords a comprehensive view of age-related modifications in muscle function. Although many clinical studies use maximal isometric strength as a marker of functional ability, the results demonstrate that there are also significant age-related modifications in ankle muscle dynamic and elastic properties.     

Activation of human quadriceps femoris during isometric, concentric, and eccentric contractions.

Maximal and submaximal activation level of the right knee-extensor muscle group were studied during isometric and slow isokinetic muscular contractions in eight male subjects. The activation level was quantified by means of the twitch interpolation technique. A single electrical impulse was delivered, whatever the contraction mode, on the femoral nerve at a constant 50 degrees knee flexion (0 degrees = full extension). Concentric, eccentric (both at 20 degrees /s velocity), and isometric voluntary activation levels were then calculated. The mean activation levels during maximal eccentric and maximal concentric contractions were 88.3 and 89.7%, respectively, and were significantly lower (P < 0.05) with respect to maximal isometric contractions (95.2%). The relationship between voluntary activation levels and submaximal torques was linearly fitted (P < 0.01): comparison of slopes indicated lower activation levels during submaximal eccentric compared with isometric or concentric contractions. It is concluded that reduced neural drive is present during 20 degrees /s maximal concentric and both maximal and submaximal eccentric contractions. These results indicate a voluntary activation dependency on both tension levels and type of muscular actions in the human knee-extensor muscle group.     

A peptide derived from the CD loop-D helix region of ciliary neurotrophic factor (CNTF) induces neuronal differentiation and survival by binding to the leukemia inhibitory factor (LIF) receptor and common cytokine receptor chain gp130

Ciliary neurotrophic factor (CNTF) induces neuronal differentiation and promotes the survival of various neuronal cell types by binding to a receptor complex formed by CNTF receptor α (CNTFRα), gp130, and the leukemia inhibitory factor (LIF) receptor (LIFR). The CD loop-D helix region of CNTF has been suggested to be important for the cytokine interaction with LIFR. We designed a peptide, termed cintrofin, that encompasses this region. Surface plasmon resonance analysis demonstrated that cintrofin bound to LIFR and gp130, but not to CNTFRα, with apparent KD values of 35 nM and 1.1 nM, respectively. Cintrofin promoted the survival of cerebellar granule neurons (CGNs), in which cell death was induced either by potassium withdrawal or H2O2 treatment. Cintrofin induced neurite outgrowth from CGNs, and this effect was inhibited by specific antibodies against both gp130 and LIFR, indicating that these receptors are involved in the effects of cintrofin. The C-terminal part of the peptide, corresponding to the D helix region of CNTF, was shown to be essential for the neuritogenic action of the peptide. CNTF and LIF induced neurite outgrowth in CGNs plated on laminin-coated slides. On uncoated slides, CNTF and LIF had no neuritogenic effect but were able to inhibit cintrofin-induced neuronal differentiation, indicating that cintrofin and cytokines compete for the same receptors. In addition, cintrofin induced the phosphorylation of STAT3, Akt, and ERK, indicating that it exerts cell signaling properties similar to those induced by CNTF and may be a valuable survival agent with possible therapeutic potential.     

Strength loss after eccentric contractions is unaffected by creatine supplementation.

This study's objective was to determine whether 14 days of dietary creatine supplementation preceding an injurious bout of eccentric contractions affect the in vivo strength loss of mouse anterior crural muscles. Three groups of nine mice each were fed a meal diet for 14 days, one group at each of three levels of creatine supplementation (i.e., 0, 0.5, and 1% creatine). Electrically stimulated concentric, isometric, and eccentric contraction torques produced about the ankle were measured both before and after a bout of 150 eccentric contractions. Tibialis anterior muscle creatine concentration was significantly increased by the supplementation, being 12% higher in the mice fed the 1% creatine diet compared with control mice. After the bout of eccentric contractions, the reductions in torque (i.e., 46-58%) were similar for the isometric contraction, all eccentric contractions, and the slow (i.e., /= 0.62). In conclusion, a moderate increase in muscle creatine concentration induced by dietary supplementation in mice does not affect the strength loss after eccentric contractions.