Sandra A. Walsh

Effect of voluntary wheel-running exercise on muscles of the mdx mouse

The purpose of this study is to determine whether dystrophin-deficient mdx mice are more susceptible to muscle injury and functional impairment than normal C57 mice when allowed to exercise voluntarily on mouse wheels. The mdx mice were significantly impaired when compared to controls as shown by functional, contractile and morphometric responses. The distance young mdx mice ran was 67-78% of young C57 mice, while adult mdx mice ran 31-48% of adult controls. After exercise the slow, oxidative soleus of young and adult mdx mice exhibited hypertrophy with no changes in strength or fatiguability, while the young C57 mice increased strength and the adults became less fatiguable. In the adult mdx mice the fast EDL, which is primarily glycolytic, exhibits slight hypertrophy with a loss of strength, while the young exhibit no changes. These results indicate that the mdx mouse adapts differently than the C57 mouse to even moderate exercise.

Effects of aging and voluntary exercise on the function of dystrophic muscle from mdx mice

To understand how exercise affects the contractile function of dystrophic muscle, we examined the effect of long-term voluntary exercise on mdx mice and related these effects to our findings in sedentary aging mice. Although the mdx mouse is the genetic homolog for Duchenne muscular dystrophy, it does not demonstrate the same progression in limb muscle dysfunction as Duchenne muscular dystrophy as it ages. We postulated that the sedentary lifestyle of this animal plays an important role in its minimal phenotypic expression. To examine the effect of exercise, eight C57BL/10 (C57) and eight mdx mice were allowed to run ad libitum for one year. Forty sedentary mdx mice and 40 sedentary C57 from one month to 18 months of age were used as controls. Contractile characteristics of the extensor digitorum longus and soleus muscles and morphometric characteristics of the mice were examined. The mdx mice ran approximately 45% fewer kilometers per day than C57 mice. Long-term voluntary running had beneficial training effects on both the old mdx mice and their C57 controls. The exercise ameliorated the age-associated loss in tension production that was observed in the soleus of sedentary mdx and sedentary C57 mice. There was a 9% reduction in the fatigability of the extensor digitorum longus muscle of the old mdx mice after the exercise. Despite these improvements, the old mdx mice exhibited significant functional deficits compared with their C57 controls. Our hypothesis, that long-term voluntary exercise would have a beneficial training effect on control mice and a deleterious effect on mdx mice as they aged, was not supported by this study. This study shows that dystrophin-less muscles from sedentary mice display significant signs of muscle damage, yet can respond beneficially to low-level voluntary running in a manner similar to that of the C57 control.

The effect of age and temperature on MDX muscle fatigue

We have studied the in vitro contractile and fatigue characteristics of extensor digitorum longus (EDL) muscles from 8‐ and 62‐week‐old dystrophin‐deficient (mdx) and control mice at 20°C and 35°C. There were no differences in fatigability at 20°C, but at 35°C the dystrophin‐deficient muscles demonstrated increased fatigability compared to controls, with the older mice exhibiting the greatest fatigue. These results suggest a temperature‐related mechanism of myofibrillar fatigue in dystrophin‐deficient EDL muscles.

Lack of effect of amitriptyline in murine myotonia.

Amitriptyline, a tricyclic antidepressant, has been reported to diminish signs of human myotonic muscular dystrophy, but has not been examined in other myotonias. Normal and myotonic (ADRmto) mice were injected acutely with either amitriptyline, phenytoin, procainamide or 0.9% saline. In addition, two groups of myotonic mice were injected chronically with either 0.9% saline or amitriptyline for 28 days. Behavior, assessed before injection using a “drop test,” was re-evaluated at 30-min intervals for up to 180 min postinjection, as well as at the end of the 28-day chronic trial. If improvement in behavior was noted, the mice were then evaluated with insertional needle electromyography (EMG) and in vitro contractility (maximal tetanic tension and relaxation time) studies. Neither acute nor chronic amitriptyline administration had any beneficial effect on behavior, EMG or contractile parameters in myotonic mice. Phenytoin abolished abnormal EMG activity and improved behavior. Procainamide improved behavior and contractility parameters but had no effect on EMG. These results confirm that the myotonic mouse is responsive to classic antimyotonic agents, but not to amitriptyline.