IL6 receptor(358)Ala variant and trans-signaling are disease modifiers in amyotrophic lateral sclerosis.

OBJECTIVE: To test the hypothesis that patients with amyotrophic lateral sclerosis (ALS) inheriting the common interleukin 6 receptor (IL6R) coding variant (Asp METHODS: An observational, case-control study of paired serum and CSF of 47 patients with ALS, 46 healthy, and 23 neurologic disease controls from the Northeastern ALS Consortium Biofluid Repository (cohort 1) was performed to determine serum levels of IL6, sIL6R, and soluble glycoprotein 130 and compared across groups and IL6R genotype. Clinical data regarding disease progression from a separate cohort of 35 patients with ALS from the Wake Forest ALS Center (cohort 2) were used to determine change in ALSFRS-R scores by genotype. RESULTS: Patients with ALS had increased CSF IL6 levels compared with healthy ( CONCLUSIONS: Theses results suggest that for individuals inheriting the IL6R C allele, the cytokine exerts a disease- and location-specific role in ALS. Follow-up, prospective studies are necessary, as this subgroup of patients may be identified as ideally responsive to IL6 receptor-blocking therapies

Primary myoblasts from POUND mice show impaired proliferation and differentiation.

<p>A. Primary myoblasts cultures from wild-type and POUND mice show a significant decrease in the proliferation and metabolic activity of myoblasts in POUND mice compared to normal wild-type mice as measured using MTS assay (left panel). B. Myoblasts from POUND mice (right panel, top micrograph) fail to differentiate normally and after 7 days do not develop into the elongate myotubes characteristic of normal, wild-type mice (right panel, bottom micrograph). C. Real-time PCR data show that that the early marker of myoblast differentiation, MyoD (left graph), and the later differentiation marker myogenin (right graph) are both significantly downregulated in myoblasts from POUND mice.</p

Relative muscle cross-sectional area and fiber number (mean, S.D.) for the hindlimb muscles of POUND and WT mice.

<p>Fiber number is calculated by dividing muscle CSA by the average fiber cross-sectional area.</p

Altered leptin signaling in POUND mice alters IGF-1 signaling in skeletal muscle.

<p>A. ELISA assays show that muscle-derived IGF-1 is significantly decreased in the hindlimb muscles (extensor digitorum longus) from leptin receptor-deficient POUND mice (left graph), whereas protein levels of myostatin in hindlimb muscle are significantly elevated in POUND mice (right graph). B. Integrated pathway analysis from mRNA array comparing gene expression in tibialis anterior muscles of POUND mice with that of normal mice. The vertical axis represents the probability that a particular gene is associated with a specific canonical pathway by chance, the higher the score on this axis the lower the probability the association between gene and pathway is by chance alone. The strongest association revealed by the analysis is between genes altered in POUND mice and those associated with IGF-1 signaling. The open blue boxes connected by the lines represent ratio values indicating the ratio of genes detected in the pathway to the total number of genes in that particular pathway. C. Heat map from reverse phase protein analysis comparing protein expression in hindlimb muscle of POUND mice with that of normal mice. Arrows indicate proteins including Akt, MAPK, and MEK that are highly expressed in muscle from normal mice (red) but not highly expressed in muscle from POUND mice (green). Western blots shown on the right are for total and phosphorylated Akt, MAPK, and MEK.</p

Leptin increases myoblast proliferation.

<p>A. Leptin-treatment (100 ng/ml) significantly increases cell proliferation and metabolic activity measured using MTS assay in primary myoblasts from mice 12 months of age. B. Leptin-treatment (100 ng/ml) also significantly increases cell proliferation and metabolic activity measured using MTS assay in primary myoblasts from mice 24 months of age. C. -treatment (100 ng/ml) significantly increases the expression of the myogenic factors MyoD and myogenin in primary myoblasts from mice 24 months of age. Leptin did not increase the expression of these factors in myoblasts from mice 12 months of age. D. Box-and-whisker plots showing ΔΔCt values (y-axis) for leptin (LEP) and leptin receptor (LEPR) expression in the soleus (SOL; top row) and extensor digitorum longus (EDL; bottom row) muscles of mice 12 and 24 months of age (x-axis). The whiskers mark the minimum and maximum values, the boxes the first and third quartiles, and the bar within the box indicates the median. Expression of the leptin receptor is not increased with age, and is significantly (P<.05) downregulated in aged soleus (SOLLEPR).</p