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1 1 Contractile dysfunction in muscle may underlie androgen-dependent 2 motor dysfunction in spinal bulbar muscular atrophy 3 4 running title : Contractile dysfunction underlies motor dysfunction in SBMA 5 6

33 34 Spinal and bulbar muscular atrophy (SBMA) is characterized by progressive muscle 35 weakness linked to a polyglutamine expansion in the androgen receptor (AR). Current evidence 36 indicates that mutant AR causes SBMA by acting in muscle to perturb its function. However, 37 information about how muscle function is impaired is scant. One fundamental question is 38 whether the intrinsic strength of muscles, an attribute of muscle independent of its mass, is 39 affected. In the current study, we assess the contractile properties of hindlimb muscles in vitro 40 from chronically diseased males of three different SBMA mouse models: a transgenic (Tg) 41 model that broadly expresses a full length human AR with 97 CAGs (97Q), a knock-in (KI) 42 model that expresses a ‘humanized’ AR containing a CAG expansion in the first exon and a Tg 43 myogenic model that overexpresses wildtype AR only in skeletal muscle fibers. We find that 44 hindlimb muscles in the two Tg models (97Q and myogenic) show marked losses in their 45 intrinsic strength and resistance to fatigue, but were minimally affected in KI males. However, 46 diseased muscles of all three models showed symptoms consistent with myotonic dystrophy 47 type 1; namely, reduced resting membrane potential and deficits in chloride channel mRNA. 48 These data indicate that muscle dysfunction is a core feature of SBMA caused by at least some 49 of the same pathogenic mechanisms as myotonic dystrophy. Thus, mechanisms controlling 50 muscle function per se independent of mass are prime targets for SBMA therapeutics. 51