SUMMARY Age-related frailty may be due to decreased skeletal muscle regeneration. The role of TGF-β molecules myostatin and GDF11 in regeneration is unclear. Recent studies showed an age-related decrease in GDF11 and that GDF11 treatment improves muscle regeneration, which were contrary to prior studies. We now show that these recent claims are not reproducible and the reagents previously used to detect GDF11 are not GDF11 specific. We develop a GDF11-specific immunoassay and show a trend toward increased GDF11 levels in sera of aged rats and humans. GDF11 mRNA increases in rat muscle with age. Mechanistically, GDF11 and myostatin both induce SMAD2/3 phosphorylation, inhibit myoblast differentiation, and regulate identical downstream signaling. GDF11 significantly inhibited muscle regeneration and decreased satellite cell expansion in mice. Given early data in humans showing a trend for an age-related increase, GDF11 could be a target for pharmacologic blockade to treat age-related sarcopenia.

[1] We have analyzed measurements of planetary ions near Mercury made by the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) Fast Imaging Plasma Spectrometer (FIPS) over the first three Mercury years of orbital observations (25 March 2011 through 31 December 2011). We determined the composition and spatial distributions of the most abundant species in the regions sampled by the MESSENGER spacecraft during that period. In particular, we here focus on altitude dependence and relative abundances of species in a variety of spatial domains. We used observed density as a proxy for ambient plasma density, because of limitations to the FIPS field of view. We find that the average observed density is 3.9 Â 10 -2 cm -3 for He 2+ , 3.4 Â 10 -4 cm -3 for He + , 8.0 Â 10 -4 cm -3 for O + -group ions, and 5.1 Â 10 -3 cm -3 for Na + -group ions. Na + -group ions are particularly enhanced over other planetary ions (He + and O + group) in the northern magnetospheric cusp (by a factor of~2.0) and in the premidnight sector on the nightside (by a factor of~1.6). Within 30 of the equator, the average densities of all planetary ions are depressed at the subsolar point relative to the dawn and dusk terminators. The effect is largest for Na + -group ions, which are 49% lower in density at the subsolar point than at the terminators. This depression could be an effect of the FIPS energy threshold. The three planetary ion species considered show distinct dependences on altitude and local time. The Na + group has the smallest e-folding height at all dayside local times, whereas He + has the largest. At the subsolar point, the e-folding height for Na + -group ions is 590 km, and that for the O + group and He + is 1100 km. On the nightside and within 750 km of the geographic equator, Na + -group ions are enhanced in the premidnight sector. This enhancement is consistent with nonadiabatic motion and may be observational evidence that nonadiabatic effects are important in Mercury's magnetosphere.

Summary A group of genes that are highly and specifically expressed in proliferating skeletal myoblasts during myogenesis was identified. Expression of one of these genes, Hmga2, increases coincident with satellite cell activation, and later its expression significantly declines correlating with fusion of myoblasts into myotubes. Hmga2 knockout mice exhibit impaired muscle development and reduced myoblast proliferation, while overexpression of HMGA2 promotes myoblast growth. This perturbation in proliferation can be explained by the finding that HMGA2 directly regulates the RNA-binding protein IGF2BP2. Add-back of IGF2BP2 rescues the phenotype. IGF2BP2 in turn binds to and controls the translation of a set of mRNAs, including c-myc, Sp1, and Igf1r. These data demonstrate that the HMGA2-IGF2BP2 axis functions as a key regulator of satellite cell activation and therefore skeletal muscle development.

ObjectiveTo identify changes in the proteome associated with onset and progression of ATTRv amyloidosis, we performed an observational, case-controlled study which compared proteomes of patients with ATTRv amyloidosis and healthy controls.MethodsPlasma levels of >1,000 proteins were measured in patients with ATTRv amyloidosis with polyneuropathy who received either placebo or patisiran in the APOLLO study and in healthy controls. The impact of patisiran on the time profile of each protein was determined by linear mixed model at 0, 9, and 18 months. Neurofilament light chain (NfL) was further assessed using an orthogonal quantitative approach.ResultsLevels of 66 proteins were significantly changed with patisiran vs placebo, with NfL change most significant (p < 10−20). Analysis of changes in protein levels demonstrated that the proteome of patisiran-treated patients trended toward healthy controls at 18 months. Healthy controls' NfL levels were 4-fold lower than in patients with ATTRv amyloidosis with polyneuropathy (16.3 vs 69.4 pg/mL, effect: −53.1 pg/mL, 95% CI [–60.5 to −45.9]). NfL levels at 18 months increased with placebo (99.5 vs 63.2 pg/mL, 36.3 pg/mL, [16.5–56.1]) and decreased with patisiran treatment (48.8 vs 72.1 pg/mL, −23.3 pg/mL, [–33.4 to −13.1]) from baseline. At 18 months, improvement in modified Neuropathy Impairment Score +7 following patisiran significantly correlated with reduced NfL (R = 0.43, [0.29–0.55]).ConclusionsFindings suggest NfL may serve as a biomarker of nerve damage and polyneuropathy in ATTRv amyloidosis, may enable earlier diagnosis of patients with ATTRv amyloidosis, and facilitate monitoring of disease progression.Classification of evidenceThis study provides Class III evidence that NfL levels may enable earlier diagnosis of polyneuropathy in patients with ATTRv amyloidosis and facilitate monitoring of disease progression.