Exercise and IGF-1 Act Synergistically to Prolong Survival in Experimental ALS

NEW YORK (Reuters Health) - In a mouse model of amyotrophic lateral sclerosis (ALS), running on an exercise wheel further boosts the increased survival associated with insulin-like growth factor-1 (IGF-1) gene therapy, investigators report.

Dr. Fred H. Gage, at the Salk Institute for Biological Studies in La Jolla, California, previously showed that IGF-1 treatment using an adeno-associated virus (AAV) vector prolongs survival in transgenic mice that overexpress superoxide dismutase-1 (SOD1), a model of ALS.

For their current report, published in the Annals of Neurology for May, Dr. Gage's group placed SOD1 mice with a running wheel, beginning before symptom onset (age 40 days) or after onset (90 days) and compared outcomes with those of sedentary mice.

Early exposure to the wheel for 2 hours/day increased median survival by 7 days (p < 0.0005) over the median survival of 122.5 days seen in nonrunning animals. Exposure for 6 and 12 hours increased median survival to 163 days and 147 days, respectively.

In a separate set of experiments, the authors showed that AAV-IGF-1 treatment increased median survival compared with controls (148 days survival versus 119 days in untreated mice). Early running without AAV-IGF-1 treatment led to a similar prolongation of survival (to 141 days).

Treatment at day 90 with AAV-IGF-1 along with early running increased survival most of all (83-day increase, to 202 days, p < 0.0001). Postponing wheel exercise to 90 days of age led to a smaller benefit in AAV-IGF-1-treated animals (survival to 156 days).

Whereas nonrunning mice exhibited a 50% decrease in the number of motor neurons in the lumbar spinal cord at 110 days compared with wild-type mice, early running, AAV-IGF-1 treatment or combined treatment was associated with no significant change in motor neuron counts, the investigators report. Both modalities decreased astrogliosis compared with sedentary, nontreated animals.

Early running, but not AAV-IGF-1 treatment, was also associated with significantly increased levels of the antiapoptotic genes Bcl-xL and Bcl-2 in the lumbar spinal cord, in comparison with wild-type animals.

None of the animals showed any significant changes in SOD1 expression, "suggesting that the therapeutic effect of running and/or IGF-1 were acting through signaling pathways versus downregulating mutant SOD1 protein," Dr. Gage's group suggests.

Summing up, the team writes, "we have shown that exercise promotes motor neuron survival, attenuates astrogliosis, improves motor function and extends survival."

They propose that "exercise in conjunction with IGF-1 gene therapy may provide the most efficacious treatment for ALS to date."

Ann Neurol 2005;57:649-655.