TARGET: Muscle Disorders



Muscle fatigue is one of the most common complaints of patients with inherited neuromuscular disorders such as muscular dystrophy. It is also the most common complaint of patients with acquired illnesses such as heart failure, cancer, and chronic fatigue syndrome, among many others.


Although exact measures have not been taken, millions of patients are affected in the United States alone. Fatigue associated with neurological disorders is challenging to study because its presence and severity are under recognized, it is difficult to measure, its pathophysiology is unclear, and its treatments are incomplete. Patients are usaually between 20 and 50 years old, and 60%-70% are female.


Dr Marks and his team have demonstrated that calcium leak via the ryanodine receptor in the sarcoplasmic reticulum is a fundamental cause of heart failure (cardiac muscle fatigue). They went on to show that in chronic heart failure this leak also occurs in skeletal muscle, which accounts for fatigue being the most common complaint in these patients. Another common complaint is shortness of breath, even in the absence of fluid in the lungs, which might be explained by fatigue in the diaphragm.


  The lactic acid theory of muscle fatigue has been questioned, and it is thought that dysregulation of calcium balance in the muscle cell results in damage and fatigue. To test this hypothesis, Marks and colleagues studied muscle fatigue in mice and were able to show that animals exposed to extreme exercise had evidence of muscle damage secondary to calcium leak across the ryanodine channel. The leak was prevented with the use of a Rycal compound. To confirm that this series of events is relevant to humans, they tested muscle biopsies from athletes who had hyperexercised and found that, indeed, their ryanodine receptors were leaky. This work was published in the Proceedings of the National Academy of Sciences in February 2008.

Current experiments are evaluating the ryanodine receptor channel leak in mice with muscular dystrophy and in other chronic disease states.

Current News


ARMGO Pharma Receives FDA Orphan Drug Designation and Rare Pediatric Disease Designation for ARM210/S48168 for the Treatment of Duchenne Muscular Dystrophy   Link to Article


ARMGO Pharma and Servier Announce Advancement of Rycal ARM210/S48168 into Clinical Stage Program Targeting Duchenne Muscular Dystrophy   Link to Article


ARMGO Pharma Receives Research Grant Award from Kennedy's Disease Association to Support Advancement of Rycal Compounds   Link to Article


ARMGO Pharma Receives $1 Million Award from MDA to Support Advancement of Rycal Compound ARM210 as a Novel Treatment for Duchenne Muscular Dystrophy   Link to Article


ARMGO Pharma, Inc. announces the appointment of Dr. Sapan Shah as CEO   Link to Article


Kushnir A, Marks AR. The ryanodine receptor in cardiac physiology and disease. Adv Pharmacol. 2010;59:1-30.   Link to Article


Kushnir A, Shan J, Betzenhauser MJ, Reiken S, Marks AR. Role of CaMKlldelta phosphorylation of the cardiac ryanodine receptor in the force frequency relationship and heart failure. Proc Natl Acad Sci U S A. 2010 Jun1;107(22):10274-9.   Link to Article


Kushnir A, Betzenhauser MJ, Marks AR. Ryanodine receptor studies using genetically engineered mice.FEBS Lett. 2010 May 17;584(10):1956-65.   Link to Article


Betzenhauser MJ, Marks AR. Ryanodine Receptor channelopathies Pflugers Arch. 2010 Jul;460(2):467-80.   Link to Article


Fauconnier J, Thireau J, Reiken S, Cassan C, Richard S, Matecki S, Marks AR,Lacampagne A.- Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy.Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1559-64.4-9.   Link to Article

Prof. Andrew Marks presentation on, "Mechanism-Based Therapies for Heart Failure and Cardiac Arrhythmias" from the Henry Stewart Talks, Series, "Calcium Signalling: Regulation, Mechanisms, Effectors, Role in Disease and Recent Advances".
Link to Presentation