Abstract
Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder caused by polyglutamine expansion in the androgen receptor (AR) and characterized by the loss of lower motor neurons. Here we investigated pathological processes occurring in muscle biopsy specimens derived from SBMA patients and, as controls, age-matched healthy subjects and patients suffering from amyotrophic lateral sclerosis (ALS) and neurogenic atrophy. We detected atrophic fibers in the muscle of SBMA, ALS and neurogenic atrophy patients. In addition, SBMA muscle was characterized by the presence of a large number of hypertrophic fibers, with oxidative fibers having a larger size compared with glycolytic fibers. Polyglutamine-expanded AR expression was decreased in whole muscle, yet enriched in the nucleus, and localized to mitochondria. Ultrastructural analysis revealed myofibrillar disorganization and streaming in zones lacking mitochondria and degenerating mitochondria. Using molecular (mtDNA copy number), biochemical (citrate synthase and respiratory chain enzymes) and morphological (dark blue area in nicotinamide adenine dinucleotide-stained muscle cross-sections) analyses, we found a depletion of the mitochondria associated with enhanced mitophagy. Mass spectrometry analysis revealed an increase of phosphatidylethanolamines and phosphatidylserines in mitochondria isolated from SBMA muscles, as well as a 50% depletion of cardiolipin associated with decreased expression of the cardiolipin synthase gene. These observations suggest a causative link between nuclear polyglutamine-expanded AR accumulation, depletion of mitochondrial mass, increased mitophagy and altered mitochondrial membrane composition in SBMA muscle patients. Given the central role of mitochondria in cell bioenergetics, therapeutic approaches toward improving the mitochondrial network are worth considering to support SBMA patients.
Highlights
Spinal and bulbar muscular atrophy (SBMA), named Kennedy’s disease, is a neuromuscular disorder characterized by the late-onset and progressive loss of motor neurons from the brainstem and spinal cord, together with skeletal muscle weakness, fasciculations, and atrophy [1]
Using hematoxylin & eosin (H&E) analysis, we detected signs of neurogenic atrophy together with myopathic changes, such as fiber splitting and increased internal nuclei (Figs. 1A and Supplementary Material, S1), as others and we have previously described in SBMA patients [19, 20] and mice [21, 22]
We found that the atrophy index was significantly (p < 0.001) increased by > 6-fold in the muscle of SBMA, amyotrophic lateral sclerosis (ALS), and neurogenic patients compared to control subjects
Summary
Spinal and bulbar muscular atrophy (SBMA), named Kennedy’s disease, is a neuromuscular disorder characterized by the late-onset and progressive loss of motor neurons from the brainstem and spinal cord, together with skeletal muscle weakness, fasciculations, and atrophy [1]. SBMA is linked to CAG expansions in the exon 1 of the gene coding for the androgen receptor (AR) [3]. In healthy subjects, this polyglutamine-encoding CAG trinucleotide tandem repeat has a length of no more than 36 repeats, and expansions over 38 cause disease. The sex specificity of SBMA is due to the higher serum levels of androgens in males compared to females [5], and is observed in transgenic and knock-in mice expressing the polyglutamineexpanded AR [5,6,7,8]. Treatment of SBMA patients with anti-androgens exerts some beneficial effects in clinical trials [13, 14], the applicability of this approach is limited by intrinsic side-effects
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