Contractile dysfunction in muscle may underlie androgen-dependent motor dysfunction in spinal bulbar muscular atrophy

J Appl Physiol (1985). 2015 Apr 1;118(7):941-52. doi: 10.1152/japplphysiol.00886.2014. Epub 2015 Feb 5.

Abstract

Spinal and bulbar muscular atrophy (SBMA) is characterized by progressive muscle weakness linked to a polyglutamine expansion in the androgen receptor (AR). Current evidence indicates that mutant AR causes SBMA by acting in muscle to perturb its function. However, information about how muscle function is impaired is scant. One fundamental question is whether the intrinsic strength of muscles, an attribute of muscle independent of its mass, is affected. In the current study, we assess the contractile properties of hindlimb muscles in vitro from chronically diseased males of three different SBMA mouse models: a transgenic (Tg) model that broadly expresses a full-length human AR with 97 CAGs (97Q), a knock-in (KI) model that expresses a humanized AR containing a CAG expansion in the first exon, and a Tg myogenic model that overexpresses wild-type AR only in skeletal muscle fibers. We found that hindlimb muscles in the two Tg models (97Q and myogenic) showed marked losses in their intrinsic strength and resistance to fatigue, but were minimally affected in KI males. However, diseased muscles of all three models showed symptoms consistent with myotonic dystrophy type 1, namely, reduced resting membrane potential and deficits in chloride channel mRNA. These data indicate that muscle dysfunction is a core feature of SBMA caused by at least some of the same pathogenic mechanisms as myotonic dystrophy. Thus mechanisms controlling muscle function per se independent of mass are prime targets for SBMA therapeutics.

Keywords: Kennedy disease; motoneuron disease; neuromuscular disease; polyglutamine/CAG repeat disease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Androgens / metabolism*
  • Animals
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muscle Contraction*
  • Muscle Strength*
  • Muscle Weakness / etiology
  • Muscle Weakness / physiopathology*
  • Muscle, Skeletal / physiopathology*
  • Muscular Disorders, Atrophic / complications
  • Muscular Disorders, Atrophic / physiopathology*

Substances

  • Androgens