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Myostatin depletion: A therapy for Ehlers‐Danlos syndrome?

Voermans et al demonstrated that the muscle weakness, myalgia, and easy fatigability reported by the majority of patients with Ehlers-Danlos syndrome (EDS) are due to direct muscle and peripheral nerve involvement, rather than to a secondary effect. In EDS patients, physical therapy that improves muscle strength around lax joints leads to better joint stability, reducing joint hypermobility and the frequency of dislocations. Therefore, the neuromuscular pathology could also be responsible, at least in part, for the musculoskeletal complications that characterize these syndromes. Recently, we reported on a patient whose medical and genetic assessment supports this assumption. He was a male patient (presently 42 years old), with a complex phenotype, in which a 75kb resolution array comparative genomic hybridization disclosed a de novo deletion spanning about 13.7Mb in the 2q31.2q23.3 region, leading to hemizygosity of many known genes, among which were COL3A1, COL5A2, and MSTN. We subsequently confirmed with real-time polymerase chain reaction experiments the deletion of these 3 genes (data not shown). Loss-of-function mutations of COL3A1 and COL5A2 genes are responsible for the dominantly inherited forms of EDS type I and IV. Instead, MSTN encodes for myostatin, a negative regulator of muscle growth also known as growth and differentiation factor 8, which is expressed mainly in skeletal muscle cells. Lossof-function mutations of one MSTN allele result in overgrowth of skeletal muscle in various mammals (including humans), and inhibition of myostatin activity increases muscle mass and strength in experimental models. According to the MSTN monosomy, the patient displayed an exceptional constitutional muscular mass (Fig 1), especially considering the absence of such favoring factors as competitive sports, hypoglycemia, and high levels of testosterone, growth hormone, and insulinlike growth factor-1. The EDS symptoms were limited to recurrent inguinal hernias and to a mild mitral valve prolapse. However, he had no muscle weakness, myalgia, or easy fatigability, and interestingly, he also had no generalized joint hypermobility or recurrent joint dislocation. We therefore hypothesize that haploinsufficiency of MSTN acts as a modifier allele that exerts a protective effect against EDS clinical manifestations in our patient. In conclusion, these findings support the hypothesis of a direct involvement of muscle damage in the pathogenesis of neuromuscular as well as musculoskeletal defects, and suggest that: 1) EDS patients could benefit from more systematic medical care of muscular function; and 2) myostatin depletion could be employed as a possible pharmacological approach. Further investigation on animal models could provide definitive support for our proposal.