Glycolytic-to-oxidative fiber-type switch and mTOR signaling activation are early-onset features of SBMA muscle modified by high-fat diet

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.

Rescue of Metabolic Alterations in AR113Q Skeletal Muscle by Peripheral Androgen Receptor Gene Silencing

“…These findings add to a growing appreciation of non-neuronal phenotypes in this disorder, and raise the possibility that targeting metabolic alterations may alleviate disease manifestations. In support of this hypothesis is recent work demonstrating that feeding mice a high fat diet diminishes aspects of the SBMA phenotype (Rocchi et al, 2016). Additional evidence suggests that enhancing anabolic support of muscle is also beneficial in SBMA mice.…”

“…Indeed, a recent report showed decreased levels of HK2, PFKFB3 and GAPDH mRNA in skeletal muscle from SBMA patients, accompanied by a glycolytic to oxidative shift in muscle fibers (Rocchi et al, 2016). These alterations may have contributed to the modest effects of exercise observed in a randomized study of SBMA patients (Shrader et al, 2015), and in the poor tolerance of SBMA patients to aerobic exercise in an observational study (Dahlqvist and Vissing, 2015).…”

Beta-agonist stimulation ameliorates the phenotype of spinal and bulbar muscular atrophy mice and patient-derived myotubes

“…Moreover, antisense oligonucleotide-mediated inhibition of AR expression in peripheral tissues, including skeletal muscle, attenuated disease manifestations in knock-in SBMA mice18. Mechanistically, polyglutamine-expanded AR causes an androgen-dependent impairment of myogenesis in SBMA patients19, and alters muscle metabolism20. Overall, this evidence supports a primary role for muscle in disease pathogenesis and candidates this tissue as a valuable target for therapy development.…”

“…The operator was blind for genotype and treatment. Treatment was started at disease onset (13 weeks of age), which is the time at which the AR113Q mice show reduced body weight and an altered pattern of gene expression20, and was ended at 27 weeks of age. Clenbuterol did not modify the survival of control mice (Fig.…”

Decreased Peak Expiratory Flow Associated with Muscle Fiber-Type Switching in Spinal and Bulbar Muscular Atrophy

“…These fibers differ from one another in oxidative/glycolytic metabolism: type I fibers are more oxidative and regulate endurance muscle strength; type IIx fibers are more glycolytic and regulate explosive muscle strength; type IIa fibers exhibit characteristics of both type I and IIx fibers [30]. Glycolytic fast-twitch fibers are preferentially vulnerable in a transgenic mouse model of SBMA and in humans with the disorder [31–33]. Results from the present study indicate that the decrease in explosive muscle strength in subjects with SBMA is strongly associated with a reduction in the number of fast-twitch muscle fibers.…”