ABSTRACT
Growth differentiation factor 11 (GDF11) and GDF8 (MSTN) are closely related TGF-ß family proteins that interact with nearly identical signaling receptors and antagonists. However, GDF11 appears to activate SMAD2/3 more potently than GDF8 in vitro and in vivo. The ligands possess divergent structural properties, whereby substituting unique GDF11 amino acids into GDF8 enhanced the activity of the resulting chimeric GDF8. We investigated potentially distinct endogenous activities of GDF11 and GDF8 in vivo by genetically modifying their mature signaling domains. Full recoding of GDF8 to that of GDF11 yielded mice lacking GDF8, with GDF11 levels â¼50-fold higher than normal, and exhibiting modestly decreased muscle mass, with no apparent negative impacts on health or survival. Substitution of two specific amino acids in the fingertip region of GDF11 with the corresponding GDF8 residues resulted in prenatal axial skeletal transformations, consistent with Gdf11-deficient mice, without apparent perturbation of skeletal or cardiac muscle development or homeostasis. These experiments uncover distinctive features between the GDF11 and GDF8 mature domains in vivo and identify a specific requirement for GDF11 in early-stage skeletal development.
Subject(s)
Bone Development , Growth Differentiation Factors , Muscle, Skeletal , Myostatin , Animals , Female , Mice , Pregnancy , Amino Acids/chemistry , Amino Acids/genetics , Bone Development/genetics , Bone Morphogenetic Proteins/genetics , Bone Morphogenetic Proteins/metabolism , Growth Differentiation Factors/genetics , Growth Differentiation Factors/chemistry , Muscle, Skeletal/growth & development , Muscle, Skeletal/metabolism , Myostatin/genetics , Myostatin/chemistry , Transforming Growth Factor beta/metabolismABSTRACT
Insulin resistance is associated with aging in mice and humans. We have previously shown that administration of recombinant GDF11 (rGDF11) to aged mice alters aging phenotypes in the brain, skeletal muscle, and heart. While the closely related protein GDF8 has a role in metabolism, limited data are available on the potential metabolic effects of GDF11 or GDF8 in aging. To determine the metabolic effects of these two ligands, we administered rGDF11 or rGDF8 protein to young or aged mice fed a standard chow diet, short-term high-fat diet (HFD), or long-term HFD. Under nearly all of these diet conditions, administration of exogenous rGDF11 reduced body weight by 3-17% and significantly improved glucose tolerance in aged mice fed a chow (~30% vs. saline) or HF (~50% vs. saline) diet and young mice fed a HFD (~30%). On the other hand, exogenous rGDF8 showed signifcantly lesser effect or no effect at all on glucose tolerance compared to rGDF11, consistent with data demonstrating that GFD11 is a more potent signaling ligand than GDF8. Collectively, our results show that administration of exogenous rGDF11, but not rGDF8, can reduce diet-induced weight gain and improve metabolic homeostasis.
Subject(s)
Aging/metabolism , Body Weight/drug effects , Bone Morphogenetic Proteins/administration & dosage , Diet, High-Fat/adverse effects , Insulin Resistance , Myostatin/administration & dosage , Aging/blood , Aging/drug effects , Animals , Bone Morphogenetic Proteins/pharmacology , Energy Metabolism/drug effects , Growth Differentiation Factors/administration & dosage , Growth Differentiation Factors/pharmacology , Male , Mice , Mice, Inbred C57BL , Myostatin/pharmacology , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacology , Signal Transduction/drug effectsABSTRACT
The annotation of six cluster N Mycobacterium smegmatis phages (Kevin1, Nenae, Parmesanjohn, ShrimpFriedEgg, Smurph, and SpongeBob) reveals regions of genomic diversity, particularly within the central region of the genome. The genome of Kevin1 includes two orphams (genes with no similarity to other phage genes), with one predicted to encode an AAA-ATPase.
ABSTRACT
Mycobacteriophages Chancellor, Mitti, and Wintermute infect Mycobacterium smegmatis mc2155 and are closely related to phages Cheetobro and Fionnbharth in subcluster K4. Genome sizes range from 57,697 bp to 58,046 bp. Phages are predicted to be temperate and to infect the pathogen Mycobacterium tuberculosis.