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Androgens and androgen-related molecules exert a plethora of functions across different tissues, mainly through binding to the transcription factor androgen receptor (AR). Despite widespread therapeutic use and misuse of androgens as potent anabolic agents, the molecular mechanisms of this effect on skeletal muscle are currently unknown. Muscle mass in adulthood is mainly regulated by the bone morphogenetic protein (BMP) axis of the transforming growth factor (TGF)-β pathway via recruitment of mothers against decapentaplegic homolog 4 (SMAD4) protein. Here we show that, upon activation, AR forms a transcriptional complex with SMAD4 to orchestrate a muscle hypertrophy programme by modulating SMAD4 chromatin binding dynamics and enhancing its transactivation activity. We challenged this mechanism of action using spinal and bulbar muscular atrophy (SBMA) as a model of study. This adult-onset neuromuscular disease is caused by a polyglutamine expansion (polyQ) in AR and is characterized by progressive muscle weakness and atrophy secondary to a combination of lower motor neuron degeneration and primary muscle atrophy. Here we found that the presence of an elongated polyQ tract impairs AR cooperativity with SMAD4, leading to an inability to mount an effective anti-atrophy gene expression programme in skeletal muscle in response to denervation. Furthermore, adeno-associated virus, serotype 9 (AAV9)-mediated muscle-restricted delivery of BMP7 is able to rescue the muscle atrophy in SBMA mice, supporting the development of treatments able to fine-tune AR-SMAD4 transcriptional cooperativity as a promising target for SBMA and other conditions associated with muscle loss.

Objective To determine whether blood biomarkers of neuronal damage (neurofilament light chain [NfL]), muscle damage (creatine kinase [CK]), and muscle mass (creatinine) are altered in spinal and bulbar muscular atrophy (SBMA) and can be used as biomarkers for disease severity. Methods In this multicenter longitudinal prospective study, plasma and serum were collected from 2 cohorts of patients with SBMA in London, United Kingdom (n = 50), and Padova, Italy (n = 43), along with disease (amyotrophic lateral sclerosis [ALS]) and healthy controls, and levels of plasma and serum NfL, CK, and creatinine were measured. Disease severity was assessed by the SBMA Functional Rating Scale and the Adult Myopathy Assessment Tool at baseline and 12 and 24 months. Results Blood NfL concentrations were increased in ALS samples, but were unchanged in both SBMA cohorts, were stable after 12 and 24 months, and were not correlated with clinical severity. Normal NfL levels were also found in a well-established mouse model of SBMA. Conversely, CK concentrations were significantly raised in SBMA compared with ALS samples, and were not correlated to the clinical measures. Creatinine concentrations were significantly reduced in SBMA, and strongly and significantly correlated with disease severity. Conclusions While muscle damage and muscle mass biomarkers are abnormal in SBMA, axonal damage markers are unchanged, highlighting the relevant primary role of skeletal muscle in disease pathogenesis. Creatinine, but not CK, correlated with disease severity, confirming its role as a valuable biomarker in SBMA.

The clinical manifestations of amyotrophic lateral sclerosis (ALS) are variable in terms of age at disease onset, site of onset, progression of symptoms, motor neuron involvement, and the occurrence of cognitive and behavioral changes. Genetic background is a key determinant of the ALS phenotype. The mortality of the disease also varies with the ancestral origin of the affected population and environmental factors are likely to be associated with ALS at least within some cohorts. Disease heterogeneity is likely underpinned by the presence of different pathogenic mechanisms. A variety of ALS animal models can be informative about the heterogeneity of the neuropathological or genetic aspects of the disease and can support the development of new therapeutic intervention. Evolving biomarkers can contribute to the identification of differing genotypes and phenotypes, and can be used to explore whether genotypic and phenotypic differences in animal models might help to provide a better definition of the heterogeneity of ALS in humans. These include neurofilaments, peripheral blood mononuclear cells, extracellular vesicles, microRNA and imaging findings. These biomarkers might predict not only the development of the disease, but also the variability in progression, although robust validation is required. A promising area of progress in modeling the heterogeneity of human ALS is represented by the use of human induced pluripotent stem cell (iPSCs)-derived motor neurons. Although the translational value of iPSCs remains unclear, this model is attractive in the perspective of replicating the heterogeneity of sporadic ALS as a first step toward a personalized medicine strategy.