Overexpression of Androgen Receptors in Target Musculature Confers Androgen Sensitivity to Motoneuron Dendrites

Huguenard, Anna L.; Fernando, Shannon M.; Monks, D. Ashley; Sengelaub, Dale R.

doi:10.1210/en.2010-1197

Cited by 30 publications

(31 citation statements)

References 83 publications

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“…Thus, treatment with testosterone might have supported muscle protein synthesis and decreased protein degradation, and the resultant decrease in protein turnover could have prevented muscle atrophy. However, by using hormone treatments identical to that used in the current study, we have previously demonstrated that the weight of the quadriceps musculature is unaffected in either male (Little et al, 2009; Verhovshek et al, 2010; Huguenard et al, 2011) or female rats (Wilson et al, 2009) by treatment with testosterone.…”

Section: Discussionmentioning

confidence: 94%

Neuroprotective effects of testosterone on motoneuron and muscle morphology following spinal cord injury

Byers

Huguenard

Kuruppu

et al. 2012

J of Comparative Neurology

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Treatment with testosterone is neuroprotective/neurotherapeutic after a variety of motoneuron injuries. Here we assessed whether testosterone might have similar beneficial effects after spinal cord injury (SCI). Young adult female rats received either sham or T9 spinal cord contusion injuries and were implanted with blank or testosterone-filled Silastic capsules. Four weeks later, motoneurons innervating the vastus lateralis muscle of the quadriceps were labeled with cholera toxin-conjugated horseradish peroxidase, and dendritic arbors were reconstructed in three dimensions. Soma volume, motoneuron number, lesion volume, and tissue sparing were also assessed, as were muscle weight, fiber cross-sectional area, and motor endplate size and density. Contusion injury resulted in large lesions, with no significant differences in lesion volume, percent total volume of lesion, or spared white or gray matter between SCI groups. SCI with or without testosterone treatment also had no effect on the number or soma volume of quadriceps motoneurons. However, SCI resulted in a decrease in dendritic length of quadriceps motoneurons in untreated animals, and this decrease was completely prevented by treatment with testosterone. Similarly, the vastus lateralis muscle weights and fiber cross-sectional areas of untreated SCI animals were smaller than those of sham-surgery controls, and these reductions were both prevented by testosterone treatment. No effects on motor endplate area or density were observed across treatment groups. These findings suggest that regressive changes in motoneuron and muscle morphology seen after SCI can be prevented by testosterone treatment, further supporting a role for testosterone as a neurotherapeutic agent in the injured nervous system.

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Section: Discussionmentioning

confidence: 94%

Neuroprotective effects of testosterone on motoneuron and muscle morphology following spinal cord injury

Byers

Huguenard

Kuruppu

et al. 2012

J of Comparative Neurology

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“…Moreover, overexpression of wild-type AR in muscle replicates polyQ disease in mouse models of SBMA, 33, 34 suggesting that an expanded polyQ tract is not the only determining factor, and expression levels of specific proteins and unique cellular contexts may also be important factors of toxicity. Our finding that high levels of wild-type AR induced by differentiation and/or DHT treatment in mouse ESCs mimic the effects of expanded polyQ AR raises a number of intriguing open questions; for instance, the issues of whether the pluripotency and differentiation of ESCs is affected by DHT treatment.…”

Section: Discussionmentioning

confidence: 99%

Androgen receptor inclusions acquire GRP78/BiP to ameliorate androgen-induced protein misfolding stress in embryonic stem cells

Yang

Hsiao

et al. 2013

Cell Death Dis

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Commitment of differentiating embryonic stem cells (ESCs) toward the various lineages is influenced by many factors, including androgens. However, the mechanisms underlying proteotoxic stress conferred by androgen receptor (AR) actions on embryonic cell fate remains unclear. Here we show that mouse ESCs display stress-related cellular phenotypes in response to androgens during early phase of differentiation. Androgen induced a significant increase in the percentage of ESCs and embryoid bodies with the intranuclear and juxtanuclear AR inclusions, which were colocalized with the E3 ubiquitin ligase, C terminus of Hsc70-interacting protein. Caspase-3 activity corresponded with AR expression, was enhanced in cells engaged more differentiation phenotypes. Androgen-mediated accumulation of AR aggregates exacerbated endoplasmic reticulum (ER) stress and rendered ESCs susceptible to apoptosis. Increasing expression levels of the ER chaperones, GRP78/BiP and GRP94, as well as ER stress markers, such as ATF6, phosphorylated PERK, GADD153/CHOP and spliced XBP-1 mRNA, were dramatically elevated in ESCs overexpressing AR. We found that androgen induced GRP78/BiP to dissociate from ATF6, and act as an AR-interacting protein, which was recruited into AR inclusions in ESCs. GRP78/BiP was also colocalized with AR inclusions in the cells of spinal bulbar muscular atrophy transgenic mouse model. Overexpression of GRP78/BiP suppressed ubiquitination of AR aggregates and ameliorated the misfolded AR-mediated cytopathology in ESCs, whereas knockdown of GRP78/BiP increased the accumulation of AR aggregates and significantly higher levels of caspase-3 activity and cell apoptosis. These results generate novel insight into how ESCs respond to stress induced by misfolded AR proteins and identify GRP78/BiP as a novel regulator of the AR protein quality control.

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“…This difference in muscle androgen receptor density appears to confer androgen sensitivity on motoneuron morphology. Unlike SNB motoneurons, the morphology of quadriceps motoneurons is normally unaffected by androgen manipulation (Huguenard et al, 2011). As described above, BDNF and trkB protein in quadriceps motoneurons decrease after castration, and the lack of a concomitant decrease in dendritic length suggests that BDNF signaling does not promote dendritic growth in this system.…”

Section: Somatic Motor Systemsmentioning

confidence: 99%

“…As described above, BDNF and trkB protein in quadriceps motoneurons decrease after castration, and the lack of a concomitant decrease in dendritic length suggests that BDNF signaling does not promote dendritic growth in this system. However, androgen sensitivity can be induced in quadriceps motoneuron dendrites by increasing androgen receptor expression in the target musculature of transgenic rats (Huguenard et al, 2011). It would be interesting to examine if the pattern of changes in BDNF levels in response to androgen manipulations in the quadriceps system of androgen receptor overexpressing transgenic rats mimics that seen in the normally androgen-sensitive SNB neuromuscular system.…”

Section: Somatic Motor Systemsmentioning

confidence: 99%

Brain-derived neurotrophic factor and androgen interactions in spinal neuromuscular systems

2013

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Neurotrophic factors and steroid hormones interact to regulate a variety of neuronal processes such as neurite outgrowth, differentiation, and neuroprotection. The coexpression of steroid hormone and neurotrophin receptor mRNAs and proteins, as well as their reciprocal regulation provides the necessary substrates for such interactions to occur. This review will focus on androgen-BDNF interactions in the spinal cord, describing androgen regulation of BDNF in neuromuscular systems following castration, androgen manipulation, and injury. Androgens interact with BDNF during development to regulate normally-occurring motoneuron death, and in adulthood, androgen-BDNF interactions are involved in the maintenance of several features of neuromuscular systems. Androgens regulate BDNF and trkB expression in spinal motoneurons. Androgens also regulate BDNF levels in the target musculature, and androgenic action at the muscle regulates BDNF levels in motoneurons. These interactions have important implications for the maintenance of motoneuron morphology. Finally, androgens interact with BDNF after injury, influencing soma size, dendritic morphology, and axon regeneration. Together, these findings provide further insight into the development and maintenance of neuromuscular systems and have implications for the neurotherapeutic/neuroprotective roles of androgens and trophic factors in the treatment of motoneuron disease and recovery from injury.

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Overexpression of Androgen Receptors in Target Musculature Confers Androgen Sensitivity to Motoneuron Dendrites

Cited by 30 publications

References 83 publications

Neuroprotective effects of testosterone on motoneuron and muscle morphology following spinal cord injury

Neuroprotective effects of testosterone on motoneuron and muscle morphology following spinal cord injury

Androgen receptor inclusions acquire GRP78/BiP to ameliorate androgen-induced protein misfolding stress in embryonic stem cells

Brain-derived neurotrophic factor and androgen interactions in spinal neuromuscular systems

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