Journal
ACTA NEUROPATHOLOGICA
Volume 132, Issue 1, Pages 127-144Publisher
SPRINGER
DOI: 10.1007/s00401-016-1550-4
Keywords
Spinal and bulbar muscular atrophy; Androgen receptor; Skeletal muscle; mTOR; Rapamycin; PGC1 alpha; High-fat diet
Categories
Funding
- Telethon-Italy
- Provincia Autonoma di Trento [TCP12013, TCR09003, TCP04009]
- Marie-Curie Reintegration Grants [FP7-256448, FP7-276981]
- Marie Curie International Outgoing Fellowships [PIOF-GA-2011-300723]
- Italian Ministry of Health [RF-2011-02350097]
- Association Francaise contre les Myopathies [18722]
- Bando Progetti Strategici di Ateneo-University of Trento
- Muscular Dystrophy Association [92333]
- National Institutes of Health [R01 NS055746]
- European Research Council [282310-MyoPHAGY]
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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 gamma coactivator 1 alpha (PGC1 alpha) 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 PGC1 alpha, 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.
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