WFIKKN2
WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 2 precursor (Growth and differentiation factor-associated serum protein 1) (GASP-1) (hGASP-1) (WAP, follistatin, immunoglobulin, Kunitz and NTR domain-containing-related protein) (WFIKKN-related protein) [GASP1] [WFIKKNRP] [UNQ9235/PRO31996]
Publications[править]
Growth and differentiation factors 8 (GDF8) and 11 (GDF11) have attracted attention as targets for rejuvenating interventions. The biological activity of these proteins may be affected by circulating antagonists such as their respective prodomains, follistatin (FST315), WFIKKN1, and WFIKKN2. Reports of the relationship of GDF8 and GDF11 and their antagonists with aging and aging phenotypes such as skeletal muscle strength have been conflicting possibly because of difficulties in measuring these proteins and polypeptides. Plasma GDF8 and GDF11 and their antagonists were measured using a multiplexed selected reaction monitoring assay and liquid chromatography-tandem mass spectrometry in 160 healthy adults aged 22-93 years. Quadriceps strength was measured by knee extensor torque using isokinetic dynamometry. Spearman correlations with age were the following: GDF11 prodomain (r = .30, p = .001), GDF11 mature protein (r = .23, p = .004), FST315 (r = .32, p < .0001), WFIKKN1 (r = -.21, p = 0.008), and WFIKKN2 (r = .18, p = .02). Independent of age, FST315 and WFIKKN1 were negatively associated with knee strength (p = .02, p = .03, respectively) in a multivariable model that included both GDF8 and GDF11 mature proteins. When measured by an antibody-free selected reaction monitoring assay, GDF8, GDF11, and their antagonists are found in the circulation in the ng/mL range. In healthy adults, plasma GDF11 and antagonists FST315, WFIKKN1, and WFIKKN2 differed by age. Antagonists of GDF8 and GDF11, but not GDF8 and GDF11, were independently associated with skeletal muscle strength. Further work is needed to characterize the relationship of these protein and polypeptides with sarcopenia-related phenotypes such as physical function and walking disability.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Biomarkers
- Bone Morphogenetic Proteins
- Carrier Proteins
- Chromatography, Liquid
- Female
- Follistatin
- Growth Differentiation Factors
- Healthy Volunteers
- Humans
- Intercellular Signaling Peptides and Proteins
- Male
- Middle Aged
- Muscle Strength
- Muscle, Skeletal
- Myostatin
- Proteins
- Tandem Mass Spectrometry
- Young Adult
Circulating polypeptides and proteins have been implicated in reversing or accelerating aging phenotypes, including growth/differentiation factor 8 (GDF8), GDF11, eotaxin, and oxytocin. These proteoforms, which are defined as the protein products arising from a single gene due to alternative splicing and PTMs, have been challenging to study. Both GDF8 and GDF11 have known antagonists such as follistatin (FST), and WAP, Kazal, immunoglobulin, Kunitz, and NTR domain-containing proteins 1 and 2 (WFIKKN1, WFIKKN2). We developed a novel multiplexed SRM assay using LC-MS/MS to measure five proteins related to GDF8 and GDF11 signaling, and in addition, eotaxin, and oxytocin. Eighteen peptides consisting of 54 transitions were monitored and validated in pooled human plasma. In 24 adults, the mean (SD) concentrations (ng/mL) were as follows: GDF8 propeptide, 11.0 (2.4); GDF8 mature protein, 25.7 (8.0); GDF11 propeptide, 21.3 (10.9); GDF11 mature protein, 16.5 (12.4); FST, 29.8 (7.1); FST cleavage form FST303, 96.4 (69.2); WFIKKN1, 38.3 (8.3); WFIKKN2, 32.2 (10.5); oxytocin, 1.9 (0.9); and eotaxin, 2.3 (0.5). This novel multiplexed SRM assay should facilitate the study of the relationships of these proteoforms with major aging phenotypes.
MeSH Terms
- Aging
- Biomarkers
- Bone Morphogenetic Proteins
- Carrier Proteins
- Chemokine CCL11
- Female
- Growth Differentiation Factors
- Humans
- Intercellular Signaling Peptides and Proteins
- Male
- Middle Aged
- Myostatin
- Oxytocin
- Phenotype
- Protein Isoforms
- Proteins
- Proteome
- Proteomics
Keywords
- Aging
- Eotaxin
- Follistatin
- Growth/differentiation factor 11
- Growth/differentiation factor 8
- Oxytocin
- WFIKKN1
- WFIKKN2