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Aims Duchenne muscular dystrophy (DMD) is an X‐linked inherited disease due to dystrophin deficiency causing skeletal and cardiac muscle dysfunction. Affected patients lose ambulation by age 12 and usually die in the second to third decades of life from cardiac and respiratory failure. Symptomatic treatment includes the use of anti‐inflammatory corticosteroids, which are associated with side effects including weight gain, osteoporosis, and increased risk of cardiovascular disease. Novel treatment options include blockade of the renin–angiotensin–aldosterone system, because angiotensin as well as aldosterone contribute to persistent inflammation and fibrosis, and aldosterone blockade represents an efficacious anti‐fibrotic approach in cardiac failure. Recent preclinical findings enabled successful clinical testing of a combination of steroidal mineralocorticoid receptor antagonists (MRAs) and angiotensin converting enzyme inhibitors in DMD boys. The efficacy of MRAs alone on dystrophic skeletal muscle and heart has not been investigated. Here, we tested efficacy of the novel non‐steroidal MRA finerenone as a monotherapy in a preclinical DMD model. Methods and results The dystrophin‐deficient, utrophin haploinsufficient mouse model of DMD was treated with finerenone and compared with untreated dystrophic and wild‐type controls. Grip strength, electrocardiography, cardiac magnetic resonance imaging, muscle force measurements, histological quantification, and gene expression studies were performed. Finerenone treatment alone resulted in significant improvements in clinically relevant functional parameters in both skeletal muscle and heart. Normalized grip strength in rested dystrophic mice treated with finerenone (40.3 ± 1.0 mN/g) was significantly higher (P = 0.0182) compared with untreated dystrophic mice (35.2 ± 1.5 mN/g). Fatigued finerenone‐treated dystrophic mice showed an even greater relative improvement (P = 0.0003) in normalized grip strength (37.5 ± 1.1 mN/g) compared with untreated mice (29.7 ± 1.1 mN/g). Finerenone treatment also led to significantly lower (P = 0.0075) susceptibility to limb muscle damage characteristic of DMD measured during a contraction‐induced injury protocol. Normalized limb muscle force after five lengthening contractions resulted in retention of 71 ± 7% of baseline force in finerenone‐treated compared with only 51 ± 4% in untreated dystrophic mice. Finerenone treatment also prevented significant reductions in myocardial strain rate (P = 0.0409), the earliest sign of DMD cardiomyopathy. Moreover, treatment with finerenone led to very specific cardiac gene expression changes in clock genes that might modify cardiac pathophysiology in this DMD model. Conclusions Finerenone administered as a monotherapy is disease modifying for both skeletal muscle and heart in a preclinical DMD model. These findings support further evaluation of finerenone in DMD clinical trials.

Introduction: We tested how a treadmill exercise program influences oxygen consumption, oxidative stress, and exercise capacity in the mdx mouse, a model of Duchenne muscular dystrophy. Methods: At age 4 weeks mdx mice were subjected to 4 weeks of twice-weekly treadmill exercise. Sedentary mdx and wild-type mice served as controls. Oxygen consumption, time to exhaustion, oxidative stress, and myofiber damage were assessed. Results: At age 4 weeks, there was a significant difference in exercise capacity between mdx and wild-type mice. After exercise, mdx mice had lower basal oxygen consumption and exercise capacity, but similar maximal oxygen consumption. Skeletal muscle from these mice displayed increased oxidative stress. Collagen deposition was higher in exercised versus sedentary mice. Conclusions: Exercised mdx mice exhibit increased oxidative stress, as well as deficits in exercise capacity, baseline oxygen consumption, and increased myofiber fibrosis. Muscle Nerve 54: 110–117, 2016

Early treatment with heart failure drugs lisinopril and spironolactone improves skeletal muscle pathology in Duchenne muscular dystrophy (DMD) mouse models. The angiotensin converting enzyme inhibitor lisinopril and mineralocorticoid receptor (MR) antagonist spironolactone indirectly and directly target MR. The presence and function of MR in skeletal muscle have not been explored. MR mRNA and protein are present in all tested skeletal muscles from both wild-type mice and DMD mouse models. MR expression is cell autonomous in both undifferentiated myoblasts and differentiated myotubes from mouse and human skeletal muscle cultures. To test for MR function in skeletal muscle, global gene expression analysis was conducted on human myotubes treated with MR agonist (aldosterone; EC50 1.3 nM) or antagonist (spironolactone; IC50 1.6 nM), and 53 gene expression differences were identified. Five differences were conserved in quadriceps muscles from dystrophic mice treated with spironolactone plus lisinopril (IC50 0.1 nM) compared with untreated controls. Genes down-regulated more than 2-fold by MR antagonism included FOS, ANKRD1, and GADD45B, with known roles in skeletal muscle, in addition to NPR3 and SERPINA3, bona fide targets of MR in other tissues. MR is a novel drug target in skeletal muscle and use of clinically safe antagonists may be beneficial for muscle diseases.—Chadwick, J. A., Hauck, J. S., Lowe, J. , Shaw, J. J., Guttridge, D. C., Gomez-Sanchez, C. E., Gomez-Sanchez, E. P., Rafael-Fortney, J. A. Mineralocorticoid receptors are present in skeletal muscle and represent a potential therapeutic target.