Abstract
Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The mechanism by which expansion of polyglutamine in AR causes muscle atrophy is unknown. Here, we investigated pathological pathways underlying muscle atrophy in SBMA knock-in mice and patients. We show that glycolytic muscles were more severely affected than oxidative muscles in SBMA knock-in mice. Muscle atrophy was associated with early-onset, progressive glycolytic-to-oxidative fiber-type switch. Whole genome microarray and untargeted lipidomic analyses revealed enhanced lipid metabolism and impaired glycolysis selectively in muscle. These metabolic changes occurred before denervation and were associated with a concurrent enhancement of mechanistic target of rapamycin (mTOR) signaling, which induced peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC1α) expression. At later stages of disease, we detected mitochondrial membrane depolarization, enhanced transcription factor EB (TFEB) expression and autophagy, and mTOR-induced protein synthesis. Several of these abnormalities were detected in the muscle of SBMA patients. Feeding knock-in mice a high-fat diet (HFD) restored mTOR activation, decreased the expression of PGC1α, TFEB, and genes involved in oxidative metabolism, reduced mitochondrial abnormalities, ameliorated muscle pathology, and extended survival. These findings show early-onset and intrinsic metabolic alterations in SBMA muscle and link lipid/glucose metabolism to pathogenesis. Moreover, our results highlight an HFD regime as a promising approach to support SBMA patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1550-4) contains supplementary material, which is available to authorized users.
Highlights
Spinal and bulbar muscular atrophy (SBMA) is an X-linked motor neuron disease characterized by late-onset degeneration of lower motor neurons and skeletal muscle atrophy [41]
The mean cross-sectional area (CSA) of oxidative fibers was decreased by 10 % in 40-day-old AR113Q mice and progressed to 16 % in 180-day-old mice, whereas that of glycolytic fibers was decreased by 10 % at 40 days of age and progressed to 40 % at 180 days of age in the quadriceps and gastrocnemius (Fig. 1d; Supplementary Fig. 4a, b)
That primary cell-autonomous degenerative processes occur in SBMA muscle is supported by multiple lines of evidence [84], including the observations that abnormalities were detected in cultured myotubes isolated from the quadriceps of SBMA patients [52], modulation of expression of non-expanded as well as polyglutamine-expanded androgen receptor (AR) in muscle modifies disease [17, 59, 77], and intervention to reduce the accumulation of polyglutamine-expanded AR selectively in muscle is beneficial in SBMA mice [70]
Summary
Spinal and bulbar muscular atrophy (SBMA) is an X-linked motor neuron disease characterized by late-onset degeneration of lower motor neurons and skeletal muscle atrophy [41]. SBMA is caused by the expansion of a polyglutamine tract in the gene encoding AR [43]. Polyglutamine expansions in specific genes are responsible for eight other neurodegenerative diseases, namely Huntington’s disease (HD), dentatorubral–pallidoluysian atrophy, and spinocerebellar ataxia (SCA) type 1, 2, 3, 6, 7, and 17 [67]. A unique feature of SBMA in the family of polyglutamine diseases is sex specificity: full manifestations are restricted to males. Sex specificity is due to the conversion of polyglutamine-expanded AR to a toxic species that occurs upon binding to its natural ligand, testosterone. Several experimental and clinical strategies to modify disease have been tested to date [81], no effective therapy for SBMA has yet been developed
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