ABSTRACT
BACKGROUND & AIMS: Growth Differentiation Factor 11 (GDF11) is an anti-aging factor, yet its role in liver diseases is not established. We evaluated the role of GDF11 in healthy conditions and in the transition from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). RESULTS: GDF11 mRNA levels positively correlated with NAFLD activity score and with CPT1, SREBP, PPARγ and Col1A1 mRNA levels, and associated to portal fibrosis, in morbidly obese patients with NAFLD/NASH. GDF11-treated mice showed mildly exacerbated hepatic collagen deposition, accompanied by weight loss and without changes in liver steatosis or inflammation. GDF11 triggered ALK5-dependent SMAD2/3 nuclear translocation and the pro-fibrogenic activation of HSC. CONCLUSIONS: GDF11 supplementation promotes mild liver fibrosis. Even considering its beneficial metabolic effects, caution should be taken when considering therapeutics that regulate GDF11. METHODS: We analyzed liver biopsies from a cohort of 33 morbidly obese adults with NAFLD/NASH. We determined the correlations in mRNA expression levels between GDF11 and genes involved in NAFLD-to-NASH progression and with pathological features. We also exposed wild type or obese mice with NAFLD to recombinant GDF11 by daily intra-peritoneal injection and monitor the hepatic pathological changes. Finally, we analyzed GDF11-activated signaling pathways in hepatic stellate cells (HSC).
Subject(s)
Bone Morphogenetic Proteins/metabolism , Growth Differentiation Factors/metabolism , Liver Cirrhosis/metabolism , Liver/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , Adult , Animals , Bone Morphogenetic Proteins/genetics , Bone Morphogenetic Proteins/toxicity , Case-Control Studies , Cell Line , Disease Progression , Female , Growth Differentiation Factors/genetics , Growth Differentiation Factors/toxicity , Hepatic Stellate Cells/metabolism , Hepatic Stellate Cells/pathology , Humans , Liver/pathology , Liver Cirrhosis/diagnosis , Liver Cirrhosis/etiology , Liver Cirrhosis/genetics , Liver Cirrhosis, Experimental/chemically induced , Liver Cirrhosis, Experimental/metabolism , Liver Cirrhosis, Experimental/pathology , Male , Mice, Inbred C57BL , Middle Aged , Non-alcoholic Fatty Liver Disease/diagnosis , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/genetics , Obesity, Morbid/complications , Obesity, Morbid/diagnosis , Signal TransductionABSTRACT
Loss of skeletal muscle mass and function results in loss of mobility for elderly patients. Novel therapies that can protect and/or restore muscle function during aging would have profound effects on the quality of life for this population. Growth differentiation factor 11 (GDF11) has been proposed as a "youthful" circulating factor that can restore cardiac, neural, and skeletal muscle functions in aging animals. However, conflicting data has been recently published that casts doubt on these assertions. We used a complex rat model of skeletal muscle injury that physiologically mimics injuries seen in patients; to investigate the ability of GDF11 and to enhance skeletal muscle regeneration after injury in older rats. Our data showed that GDF11 treatment resulted in a significant increase in tissue fibrosis, accompanied by attenuated functional recovery, as compared to animals treated with vehicle alone. GDF11 impaired the recovery of skeletal muscle function in older rats after injury.
Subject(s)
Aging/physiology , Bone Morphogenetic Proteins/toxicity , Growth Differentiation Factors/toxicity , Muscle, Skeletal/metabolism , Regeneration/physiology , Animals , Bone Morphogenetic Proteins/administration & dosage , Disease Models, Animal , Fibrosis , Growth Differentiation Factors/administration & dosage , Humans , Male , Muscle, Skeletal/injuries , Quality of Life , Rats , Rats, Inbred LewABSTRACT
BACKGROUND: Duchenne muscular dystrophy (DMD) is an inherited lethal muscle wasting disease characterized by cycles of degeneration and regeneration, with no effective therapy. Growth differentiation factor 11 (GDF11), a member of the TGF-ß superfamily and myostatin homologous, has been reported to have the capacity to reverse age-related skeletal muscle loss. These initial findings led us to investigate the ability of GDF11 to promote regeneration in the context of muscular dystrophy and determine whether it could be a candidate to slow down or reverse the disease progression in DMD. RESULTS: Here, we delivered recombinant GDF11 (rGDF11) to dystrophin-deficient mice using the intra-peritoneal route for 30 days and evaluated histology and function in both steady-state and cardiotoxin-injured muscles. Our data confirmed that treatment with rGDF11 resulted in elevated levels of this factor in the circulation. However, this had no effect on muscle contractility nor on muscle histology. Moreover, no difference was found in the number of regenerating myofibers displaying centrally located nuclei. On the other hand, we did observe increased collagen content, which denotes fibrosis, in the muscles of rGDF11-treated dystrophic mice. CONCLUSIONS: Taken together, our findings indicate no beneficial effect of treating dystrophic mice with rGDF11 and raise caution to a potential harmful effect, as shown by the pro-fibrotic outcome.
Subject(s)
Bone Morphogenetic Proteins/pharmacology , Growth Differentiation Factors/pharmacology , Muscle, Skeletal/drug effects , Muscular Dystrophy, Duchenne/drug therapy , Animals , Bone Morphogenetic Proteins/administration & dosage , Bone Morphogenetic Proteins/toxicity , Disease Models, Animal , Fibrosis , Growth Differentiation Factors/administration & dosage , Growth Differentiation Factors/toxicity , Injections, Intraperitoneal , Male , Mice, Inbred mdx , Muscle Contraction/drug effects , Muscle Development/drug effects , Muscle Fibers, Skeletal/drug effects , Muscle Fibers, Skeletal/pathology , Muscle Strength/drug effects , Muscle, Skeletal/pathology , Muscle, Skeletal/physiopathology , Muscular Dystrophy, Duchenne/genetics , Muscular Dystrophy, Duchenne/pathology , Muscular Dystrophy, Duchenne/physiopathology , Recombinant Proteins/pharmacology , Regeneration/drug effects , Time FactorsABSTRACT
This "Controversies in Cardiovascular Research" article evaluates the evidence for and against the hypothesis that the circulating blood level of growth differentiation factor 11 (GDF11) decreases in old age and that restoring normal GDF11 levels in old animals rejuvenates their skeletal muscle and reverses pathological cardiac hypertrophy and cardiac dysfunction. Studies supporting the original GDF11 hypothesis in skeletal and cardiac muscle have not been validated by several independent groups. These new studies have either found no effects of restoring normal GDF11 levels on cardiac structure and function or have shown that increasing GDF11 or its closely related family member growth differentiation factor 8 actually impairs skeletal muscle repair in old animals. One possible explanation for what seems to be mutually exclusive findings is that the original reagent used to measure GDF11 levels also detected many other molecules so that age-dependent changes in GDF11 are still not well known. The more important issue is whether increasing blood [GDF11] repairs old skeletal muscle and reverses age-related cardiac pathologies. There are substantial new and existing data showing that GDF8/11 can exacerbate rather than rejuvenate skeletal muscle injury in old animals. There is also new evidence disputing the idea that there is pathological hypertrophy in old C57bl6 mice and that GDF11 therapy can reverse cardiac pathologies. Finally, high [GDF11] causes reductions in body and heart weight in both young and old animals, suggestive of a cachexia effect. Our conclusion is that elevating blood levels of GDF11 in the aged might cause more harm than good.
