Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA200

Poster Communications

MuRF1 and MuRF2 independently act to mediate muscle wasting in mice with cardiac cachexia

T. Bowen1, T. Nguyen2, S. Werner2, S. Labeit3, V. Adams4

1. School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom. 2. Leipzig Heart Center, Leipzig, Germany. 3. Universitätsklinikum Mannheim, Mannheim, Germany. 4. Dresden Heart Center, Dresden, Germany.


Patients with cardiac cachexia are characterized by a severe loss of muscle mass, which reduces strength to limit mobility and quality of life. The mechanisms mediating muscle loss in cardiac cachexia however remain poorly established. Evidence indicates a key role for the muscle-specific ubiquitin E3 ligase muscle RING finger 1 (MuRF1), which is supported by this atrogin being consistently activated in acute wasting conditions. We have collected initial data to also show the second MuRF family member, MuRF2, is activated during cardiac cachexia. The current study, therefore, aimed to investigate whether both MuRF1 and MuRF2 can act independently to mediate muscle atrophy during cardiac cachexia. C57BL/6 wild-type (WT) mice (n=21) were compared to global MuRF1 (n=23) or MuRF2 (n=20) knockouts. Mice in each group were randomized to either weekly saline or monocrotaline (600 mg/kg) treatment (both i.p.). After 8 weeks, fibre cross-sectional area was measured using standard histology, while in vitro contractile function was assessed by direct stimulation. Protein expression (arbitrary units; a.u.) was determined by Western blot from muscle homogenates. Values are presented as mean±SEM and were assessed by unpaired t-test. Compared to saline-treated controls, mice treated with monocrotaline developed cardiac cachexia, with evidence of weight loss, pulmonary congestion, and right-ventricular hypertrophy (P<0.05). Compared to controls, the protein expression of both MuRF1 (0.12±0.01 vs. 0.21±0.02 a.u.) and MuRF2 (0.22±0.04 vs. 0.38±0.04 a.u.) was elevated (P<0.05) in muscle of WT mice with cardiac cachexia. Only WT mice with cardiac cachexia demonstrated muscle atrophy compared to saline-treated controls: muscle wet-weights of the soleus and tibialis anterior were reduced (P<0.05) by 11±3% and 13±3% respectively, while TA fibre cross-sectional area was reduced (P<0.05) by 32±6%. No differences (P>0.05) in muscle wet-weights or fibre cross-sectional area were observed in MuRF1/2 knockout mice with cardiac cachexia when compared to matched-controls. Maximal contractile force in the soleus of WT mice with cardiac cachexia was reduced (P<0.05) by 16±2% compared to controls, yet no impairments were developed in MuRF1/2 knockouts. Loss of muscle mass and function induced by cardiac cachexia was prevented in mice with a genetic deletion in MuRF1 or MuRF2. Overall, therefore, these data indicate that both MuRF family members, 1 and 2, can act independently to mediate muscle loss in cardiac cachexia.

Where applicable, experiments conform with Society ethical requirements