Abstract
Aberrant autonomic signaling is being increasingly recognized as an important symptom in neuromuscular disorders. The δ-sarcoglycan-deficient BIO TO-2 hamster is recognized as a good model for studying mechanistic pathways and sequelae in muscular dystrophy and heart failure, including autonomic nervous system (ANS) dysfunction. Recent studies using the TO-2 hamster model have provided promising preclinical results demonstrating the efficacy of gene therapy to treat skeletal muscle weakness and heart failure. Methods to accelerate preclinical testing of gene therapy and new drugs for neuromuscular diseases are urgently needed. The purpose of this investigation was to demonstrate a rapid non-invasive screen for characterizing the ANS imbalance in dystrophic TO-2 hamsters. Electrocardiograms were recorded non-invasively in conscious ∼9-month old TO-2 hamsters (n = 10) and non-myopathic F1B control hamsters (n = 10). Heart rate was higher in TO-2 hamsters than controls (453 ± 12 bpm vs. 311 ± 25 bpm, P < 0.01). Time domain heart rate variability, an index of parasympathetic tone, was lower in TO-2 hamsters (12.2 ± 3.7 bpm vs. 38.2 ± 6.8, P < 0.05), as was the coefficient of variance of the RR interval (2.8 ± 0.9% vs. 16.2 ± 3.4%, P < 0.05) compared to control hamsters. Power spectral analysis demonstrated reduced high frequency and low frequency contributions, indicating autonomic imbalance with increased sympathetic tone and decreased parasympathetic tone in dystrophic TO-2 hamsters. Similar observations in newborn hamsters indicate autonomic nervous dysfunction may occur quite early in life in neuromuscular diseases. Our findings of autonomic abnormalities in newborn hamsters with a mutation in the δ-sarcoglycan gene suggest approaches to correct modulation of the heart rate as prevention or therapy for muscular dystrophies.
Highlights
Neuromuscular diseases, routinely considered with regard to muscle weakness, frequently affect the heart and the cardiovascular system
We recorded ECGs non-invasively in 10 conscious F1B control hamsters and 10 TO-2 δ-sarcoglycan-deficient hamsters, an animal model used routinely to test the efficacy of new therapies in treating muscular dystrophies and heart failure
The data we obtained non-invasively in awake neonatal δ-sarcoglycan-deficient TO-2 hamsters suggest that the autonomic nervous system (ANS) abnormalities clearly apparent in older moribund myopathic TO-2 animals may commence very early in life
Summary
Neuromuscular diseases, routinely considered with regard to muscle weakness, frequently affect the heart and the cardiovascular system. Duchenne’s muscular dystrophy and some LGMD, childhood muscle disorders resulting from loss of expression of sarcoglycans, are both characterized by similar aberrant autonomic modulation of the heart in animal models (Giudice et al, 2000; Chu et al, 2002). We sought to determine if there is evidence of autonomic nervous system (ANS) abnormalities early in the life of δ-sarcoglycan-deficient hamsters, a model of LGMD characterized by definitive histopathological and clinical sequelae of skeletal muscle pathology and heart failure late in life (Straub et al, 1998; Xiao et al, 2000; Zhu et al, 2005; Kato et al, 2006; Hoshijima et al, 2011)
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