Glycolytic-to-oxidative fiber-type switch and mTOR signaling activation are early-onset features of SBMA muscle modified by high-fat diet.
Anna RocchiCarmelo MiliotoSara ParodiAndrea ArmirottiDoriana BorgiaMatteo PellegriniAnna UrciuoloSibilla MolonValeria MorbidoniManuela MarabitaVanina RomanelloPamela GattoBert BlaauwPaolo BonaldoFabio SambataroDiane M RobinsAndrew P LiebermanGianni SorarùLodovica VerganiMarco SandriMaria PennutoPublished in: Acta neuropathologica (2016)
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.
Keyphrases
- early onset
- high fat diet
- skeletal muscle
- end stage renal disease
- late onset
- insulin resistance
- ejection fraction
- newly diagnosed
- poor prognosis
- chronic kidney disease
- adipose tissue
- transcription factor
- peritoneal dialysis
- cell proliferation
- oxidative stress
- high fat diet induced
- squamous cell carcinoma
- spinal cord injury
- multiple sclerosis
- mass spectrometry
- diabetic rats
- cell death
- simultaneous determination
- high resolution
- endoplasmic reticulum stress
- single molecule
- gas chromatography mass spectrometry
- drug induced