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  • Meeting abstract
  • Open Access

Soluble guanylyl cyclase regulates skeletal muscle fiber type plasticity, fatigue resistance and whole body insulin resistance

  • 1,
  • 1,
  • 2,
  • 3,
  • 4,
  • 2, 5 and
  • 1Email author
BMC Pharmacology and Toxicology201516 (Suppl 1) :A8

  • Published:


  • Duchenne Muscular Dystrophy
  • Muscle Fatigue
  • Duchenne Muscular Dystrophy
  • Guanylyl Cyclase
  • Duchenne Muscular Dystrophy Patient

Pathogenic defects in NO-cGMP signaling drive skeletal muscle dysfunction in Duchenne muscular dystrophy (DMD). These defects arise from decreased nNOS and guanylyl cyclase (GC) activity and loss of spatial control of NO production. Therapeutics such as sildenafil that amplify NO-cGMP signaling reduce skeletal muscle dysfunction in DMD patients and mouse models of DMD making GC and cGMP attractive therapeutic targets. However, GC and cGMP functions in skeletal muscle are poorly defined hindering therapy development. To remove this barrier, we investigated the functions of GC in skeletal muscle.

We report that α1β1 soluble GC (sGC) is the primary cGMP source in skeletal muscle. α1β1 sGC expression was greater in oxidative muscles suggesting a greater cGMP synthesis capacity and muscle-specific differences in sGC function. Interestingly, sGC activity exhibited partial nNOS dependence. Analyses of sGC subcellular localization revealed a pool of α1β1 at the cis-Golgi complex in muscle cells. α1β1 and α2β1 sGC localized to the microvasculature. Muscles lacking a functional α1 sGC subunit (α1β1 sGC deficient) exhibited reduced fatigue resistance and normal hypertrophic growth. Surprisingly, α1β1 sGC deficiency had no impact on mitochondrial content suggesting that mitochondrial density may not be as tightly regulated by cGMP as previously thought. α1β1 sGC deficiency had a modest effect on mitochondrial ATP synthesis. Also, loss of α1β1 sGC triggered a type IIA to type IIX fiber shift. Although this shift was unlikely to significantly enhance fatigability, it may impact insulin metabolism because type IIX fiber content positively correlates with insulin insensitivity. Indeed, α1β1 sGC null mice exhibited gender-specific defects in whole body insulin sensitivity consistent with reports of gender-specific effects of cGMP on metabolism but normal glucose tolerance indicating compensatory changes in glucose metabolism.

In summary, these findings argue that NO signaling through sGC plays important roles in muscle fatigue and fiber type specification and suggest sGC as a target for mitigating skeletal muscle fatigue in DMD. These data also suggest that disruption of NO-cGMP signaling may contribute to the poorly understood metabolic defects in DMD patients. By showing that reductions in cGMP synthesis promote muscle fatigue, type IIX content and insulin resistance, these data suggest new insights as to how decreases in cGMP may contribute to the development of metabolic dysfunction and disease, particularly over time. Importantly, these results suggest sGC as a potential target for mitigating insulin resistance.

Authors’ Affiliations

Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Department of Bioengineering, University of Washington, Seattle, WA 98109, USA
Department for Molecular Biomedical Research and Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium
Department of Anesthesia, Critical Care and Pain Medicine, Anesthesia Center for Critical Care Research, Massachusetts General Hospital, Boston, MA 02114, USA
Department of Radiology, University of Washington, Seattle, WA 98109, USA


© Moon and Balke et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.