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Reducing systemic hypermetabolism by inducing hypothyroidism does not prolong survival in the SOD1-G93A mouse
Jia Li1, Jill M Paulson, Felix D Ye
1Department of Neurology and Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Abstract:
ALS is commonly associated with a hypermetabolic state. In this study, we assess whether inhibition of this hypermetabolism via the induction of hypothyroidism can forestall disease onset and prolong life in the SOD1-G93A mouse. We treated a cohort of 16 SOD1-G93A mice with methimazole, a potent inhibitor of thyroid hormone synthesis and followed a second group of 23 untreated littermate control animals from approximately five weeks of age onward. Total thyroxine (T4) levels, weights, and rectal temperatures were obtained on a regular basis and animals were sacrificed when they were no longer able to feed themselves. Results revealed that T4 levels were effectively suppressed within two weeks of drug initiation. However, there was no significant difference between the two groups either in terms of clinical disease onset (120.1±9.3 days for treated animals and 116.7±6.3 days for untreated animals) or in terms of survival (131.4±11.7 days for treated animals and 134.0±10.0 days for untreated animals). A correlation analysis between mean T4 levels for each animal versus survival showed that, contrary to our hypothesis, higher T4 levels correlated with longer survival. In conclusion, these studies show that drug-induced hypothyroidism does not alter the disease course in the SOD1-G93A ALS mouse.
Insights
Inducing hypothyroidism in SOD1-G93A mice did not delay Amyotrophic Lateral Sclerosis (ALS) onset or improve survival. Contrary to expectations, higher thyroxine levels correlated with longer survival in this ALS mouse model.
Area of Science:
- Neuroscience
- Endocrinology
- Genetics
Background:
- Amyotrophic Lateral Sclerosis (ALS) is often linked to a hypermetabolic state.
- Investigating metabolic interventions may offer therapeutic strategies for ALS.
Purpose of the Study:
- To determine if inducing hypothyroidism can delay disease onset and extend survival in the SOD1-G93A mouse model of ALS.
- To assess the relationship between thyroid hormone levels and disease progression in ALS.
Main Methods:
- SOD1-G93A mice were treated with methimazole to induce hypothyroidism.
- Thyroxine (T4) levels, weight, and temperature were monitored regularly.
- Disease onset and survival were recorded until animals could no longer self-feed.
Main Results:
- Methimazole effectively suppressed T4 levels within two weeks.
- No significant differences in clinical disease onset or survival were observed between hypothyroid and control groups.
- Higher T4 levels unexpectedly correlated with longer survival, contradicting the initial hypothesis.
Conclusions:
- Drug-induced hypothyroidism does not alter disease progression or survival in the SOD1-G93A ALS mouse model.
- The hypermetabolic state in ALS may not be directly targetable by hypothyroidism for therapeutic benefit.
- Further research is needed to understand the complex role of thyroid hormones in ALS pathogenesis.
