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

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.

Beta-agonist stimulation ameliorates the phenotype of spinal and bulbar muscular atrophy mice and patient-derived myotubes

“…As control, we used wild type sibling mice. AR113Q mice develop muscle atrophy starting around 8–12 weeks of age, show reduced muscle force and altered motor function, and about 50% of them die prematurely from urinary tract obstructions by 30 weeks of age1343. Treatment of the mice with clenbuterol was performed by oral gavage 3 days/week to avoid receptor desensitization, using a “low” dose (1 mg/kg) and a “high” dose (2 mg/kg) of clenbuterol.…”

Polyglutamine-expanded androgen receptor disrupts muscle triad, calcium dynamics and the excitation-contraction coupling gene expression program

“…This feature is invariably recapitulated in all the animal models of SBMA, including those used here. Moreover, force decay is accompanied by a profound alteration in the kinetics of muscle contractility (29,52). However, a clear mechanism explaining these alterations and how they affect force in SBMA muscle was still missing.…”

“…Early muscle pathology and clear signs of myopathy are present in patients, including elevated levels of serum creatine kinase (CK), myofiber degeneration and structures similar to central cores detected before clinical symptoms (25)(26)(27)(28). Likewise, signs of myopathy and reduced intrinsic muscle force precede spinal cord pathology also in transgenic and knock-in mouse models of SBMA (11,29). Interestingly, fast-twitch muscles were mainly affected and displayed a glycolytic-to-oxidative fiber-type switch with alterations in lipid homeostasis regardless of denervation (30).…”

The effect of NAMPT deletion in projection neurons on the function and structure of neuromuscular junction (NMJ) in mice

“…Loss of NAMPT in projection neurons alters skeletal muscle contractile responses. Disabled synaptic transmission in the motor terminal at the NMJ has been suggested to affect muscle function 35,36 . To NAD + levels in semitendinosus and gastrocnemius muscles of control mice after NMN administration.…”