AR cooperates with SMAD4 to maintain skeletal muscle homeostasis.
Mitra ForouhanWooi Fang LimLaura C Zanetti-DominguesChristopher J TynanThomas C RobertsBilal MalikRaquel ManzanoAlfina A SpecialeRuth ElleringtonAntonio Garcia-GuerraPietro FrattaGianni SorarúLinda GreensmithMaria PennutoMatthew J A WoodCarlo RinaldiPublished in: Acta neuropathologica (2022)
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.
Keyphrases
- skeletal muscle
- transforming growth factor
- epithelial mesenchymal transition
- gene expression
- transcription factor
- insulin resistance
- signaling pathway
- multiple sclerosis
- mesenchymal stem cells
- dna methylation
- dna binding
- genome wide
- spinal cord
- randomized controlled trial
- chronic pain
- spinal cord injury
- oxidative stress
- high fat diet induced
- gene therapy
- adipose tissue
- heat shock
- binding protein
- amino acid
- high intensity
- heat shock protein
- protein protein