Abstract
BackgroundPulmonary hypertension leads to right ventricular heart failure and ultimately to cardiac cachexia. Cardiac cachexia induces skeletal muscles atrophy and contractile dysfunction. MAFbx and MuRF1 are two key proteins that have been implicated in chronic muscle atrophy of several wasting states.MethodsMonocrotaline (MCT) was injected over eight weeks into mice to establish pulmonary hypertension as a murine model for cardiac cachexia. The effects on skeletal muscle atrophy, myofiber force, and selected muscle proteins were evaluated in wild-type (WT), MuRF1, and MuRF2-KO mice by determining muscle weights, in vitro muscle force and enzyme activities in soleus and tibialis anterior (TA) muscle.ResultsIn WT, MCT treatment induced wasting of soleus and TA mass, loss of myofiber force, and depletion of citrate synthase (CS), creatine kinase (CK), and malate dehydrogenase (MDH) (all key metabolic enzymes). This suggests that the murine MCT model is useful to mimic peripheral myopathies as found in human cardiac cachexia. In MuRF1 and MuRF2-KO mice, soleus and TA muscles were protected from atrophy, contractile dysfunction, while metabolic enzymes were not lowered in MuRF1 or MuRF2-KO mice. Furthermore, MuRF2 expression was lower in MuRF1KO mice when compared to C57BL/6 mice.ConclusionsIn addition to MuRF1, inactivation of MuRF2 also provides a potent protection from peripheral myopathy in cardiac cachexia. The protection of metabolic enzymes in both MuRF1KO and MuRF2KO mice as well as the dependence of MuRF2 expression on MuRF1 suggests intimate relationships between MuRF1 and MuRF2 during muscle atrophy signaling.
Highlights
Pulmonary hypertension leads to right ventricular heart failure and to cardiac cachexia
Comparison of cachexia response to MCT stress in WT, Muscle ring finger protein 1 (MuRF1), Muscle ring finger protein 2 (MuRF2) KO mice Weekly injections of MCT into WT mice are suitable to establish a chronic cardiac cachexia condition as previously described: MCT treatment of WT animals for 8 weeks resulted in increased lung weight (Fig. 1a), increased heart weight (Fig. 1b), and right
In the present study we investigated in mouse models the roles of MuRF1 and MuRF2 for the development of muscle atrophy and muscle dysfunction in a right ventricular heart failure setting that mimics human heart failure during chronic pulmonary hypertension
Summary
Pulmonary hypertension leads to right ventricular heart failure and to cardiac cachexia. Cardiac cachexia induces skeletal muscles atrophy and contractile dysfunction. MAFbx and MuRF1 are two key proteins that have been implicated in chronic muscle atrophy of several wasting states. Nguyen et al Skeletal Muscle (2020) 10:12 lysosomal proteolysis and the ubiquitin proteasome system (UPS) are recognized to play important roles in the protein breakdown. The UPS system and relevant ubiquitin E3-ligases are discussed as potential targets to modulate skeletal muscle atrophy. Performing transcript profiling in several atrophy models identified MuRF1 and MAFbx as ubiquitin E3 ligases only expressed in heart and skeletal muscle [11]. MuRF1 knockout animal’s exhibit resistance towards the development of skeletal muscle atrophy [11, 13] and when subjected to chronic pressure overload the animals developed massive cardiac hypertrophy [14]. MuRF3 binds to microtubules helping to develop a network resistant to depolarization [18], plays a role in myosin protein quality control [19] and protects against diabetic cardiomyopathy [20]
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