Treating the Heart Versus Treating Skeletal Muscle

In DMD and many other types of muscular dystrophies, cardiac and skeletal muscles are both compromised. The interplay between heart disease and skeletal muscle disease remains to be fully appreciated. It is generally agreed that normalizing skeletal muscle function alone cannot halt heart disease (Muntoni et al. 1995; Towbin et al. 1993; Townsend et al. 2007; Zhu et al. 2002). Limb muscles and respiratory muscles (in particular, the diaphragm) are auxiliary pumps that promote venous return. When skeletal muscle contractility is severely compromised (such as in m-dko mice), cardiac output will decrease as a consequence of reduced venous return. This seems to suggest that treating skeletal muscle alone should increase cardiac output and improve heart function. If left unchecked, severe skeletal muscle disease will aggravate cardiomyopathy. This argument is supported by findings from two clinical studies (Hunsaker et al. 1982; Matsuda et al. 1977). Hunsaker et al. (1982) followed nine ambulant DMD patients for 10 years. Interestingly only the patients who became wheelchair-bound (suggesting a more severe skeletal muscle disease) developed heart disease. The remaining patients showed no clinical symptoms of heart disease and their heart function was significantly better, according to echocardiography examinations. Matsuda et al. (1977) found similar results in a larger group of patients (57 patients). Experimental evidence for this hypothesis comes from m-dko mice (Megeney et al. 1999). MyoD is involved in skeletal, but not cardiac, muscle regeneration. As expected, m-dko mice develop much severer skeletal muscle disease (Megeney et al. 1996). Surprisingly, they also show anatomical and histological signs of dilated cardiomyopathy (Duan 2006a; Megeney et al. 1999). Hence, both mouse results and clinical observations seem to suggest that exaggerated skeletal muscle disease induces and/or precipitates hidden heart disease.

On the other hand, patients with mild skeletal muscle disease are generally capable of greater physical activity. It is thus quite conceivable that these physical activities may place more stress on the heart and worsen cardiomyopathy. Based on this theory, ameliorating skeletal muscle disease may encourage more physical activities, and consequently, lead to untoward heart damage. When patients are immobilized by severe skeletal muscle disease, the reduced physical activity will also reduce cardiac demand. Hence, heart disease will not get worse in these patients. In support of this view, several clinical studies have found no increase in severity of Duchenne cardiomyopathy in patients who suffered from more severe skeletal muscle disease (Angelini et al. 1996; Brockmeier et al. 1998; Nigro et al. 1995; Takenaka et al. 1993; Utsunomiya et al. 1990). A recent mouse study also found that transgenic amelioration of skeletal muscle disease alone increased physical activity and worsened heart function (Townsend et al. 2008).

Taken together, these findings suggest that worsening of skeletal muscle disease may promote heart deterioration in untreated patients. However, if patients were only treated for the skeletal muscle problem, they may end up facing more severe heart disease. Similarly, if patients were only treated for cardiomyopathy, they may not achieve full cardiac recovery (Bostick et al. 2009). We believe that an effective therapy for Duchenne cardiomyopathy should treat both skeletal muscle disease and cardiomyopathy simultaneously.

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