2020 Research

Muscle BDNF improves synaptic and contractile muscle strength in Kennedy's disease mice in a muscle‐type specific manner.

We report that a muscle‐derived neurotrophic factor, BDNF, rescues synaptic and muscle function in a muscle‐type specific manner in mice modelling Kennedy's disease (KD). We also find that BDNF rescues select molecular mechanisms in slow and fast muscle that may underlie the improved cellular function. We also report for the first time that expression of BDNF, but not other members of the neurotrophin family, is perturbed in muscle from patients with KD. To read the article, click here.

MEF2 impairment underlies skeletal muscle atrophy in polyglutamine disease

We find no evidence to suggest dysfunction of signaling pathways that trigger muscle hypertrophy or impairment of the muscle stem cell niche. Instead, we find that skeletal muscle atrophy is characterized by diminished function of the transcriptional regulator Myocyte Enhancer Factor 2 (MEF2), a regulator of myofiber homeostasis. Decreased expression of MEF2 target genes is age- and glutamine tract length-dependent, occurs due to polyQ AR proteotoxicity, and is associated with sequestration of MEF2 into intranuclear inclusions in muscle. To read the article, click here.

Enhanced Clearance of Neurotoxic Misfolded Proteins by the Natural Compound Berberine and Its Derivatives

We tested the natural alkaloid berberine (BBR) and some derivatives for their capability to enhance misfolded protein clearance in cell models of NDs, evaluating which degradative pathway mediates their action. Results: We found that both BBR and its semisynthetic derivatives promote degradation of mutant androgen receptor (ARpolyQ) causative of spinal and bulbar muscular atrophy, acting mainly via proteasome and preventing ARpolyQ aggregation. To read the article, click here.

Deterioration of muscle force and contractile characteristics are early pathological events in spinal and bulbar muscular atrophy mice

To fully characterise the role of muscle in SBMA, we undertook a longitudinal physiological and histological characterisation of disease progression in the AR100 mouse model of SBMA. Our results show that the disease first manifests in skeletal muscle, prior to any motor neuron degeneration, which only occurs in late stage disease. These findings reveal alterations in muscle function, including reduced muscle force and changes in contractile characteristics, are early pathological events in SBMA mice and suggest that muscle-targeted therapeutics may be effective in SBMA. To read the article. Click here.

Unveiling synapse pathology in spinal bulbar muscular atrophy by genome-wide transcriptome analysis of purified motor neurons derived from disease specific iPSCs

Although ligand (testosterone)-dependent mutant AR aggregation has been shown to play important roles in motor neuronal degeneration by the analyses of transgenic mice models and in vitro cell culture models, the underlying disease mechanisms remain to be fully elucidated because of the discrepancy between model mice and SBMA patients. ...we established disease specific iPSCs from four SBMA patients, and differentiated them into spinal motor neurons. The results revealed the involvement of the pathology associated with synapses, epigenetics, and endoplasmic reticulum (ER) in SBMA. To read the article. Click here.

Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism

 We generated new mouse models of SBMA for constitutive and inducible expression of mutant AR and performed biochemical, histological and functional analyses of phenotype. We show that polyQ-expanded AR causes motor dysfunction, premature death, IIb-to-IIa/IIx fiber-type change, glycolytic-to-oxidative fiber-type switching, upregulation of atrogenes and autophagy genes and mitochondrial dysfunction in skeletal muscle, together with signs of muscle denervation at late stage of disease.

Finally, we found that two-week induction of expression of polyQ-expanded AR in adult mice was sufficient to cause premature death, body weight loss and muscle atrophy, but not aggregation, metabolic alterations, motor coordination and fiber-type switch, indicating that expression of the disease protein in the adulthood is sufficient to recapitulate several, but not all SBMA manifestations in mice. These results imply that chronic expression of polyQ-expanded AR, i.e. during development and prepuberty, is key to induce the full SBMA muscle pathology observed in patients. To read the article. Click here.