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Introduction Recent in vitro studies suggest that CAPN3 deficiency leads initially to accelerated myofiber formation followed by depletion of satellite cells (SC). In normal muscle, upregulation of miR-1 and miR-206 facilitates transition from proliferating SCs to differentiating myogenic progenitors.

Sporadic inclusion-body myositis (sIBM) is the most common idiopathic inflammatory myopathy affecting those >50 years of age.1,2 Typically, onset is characterized by insidious and frequently asymmetrical weakness of the arms and legs, which is often erroneously attributed to aging and can therefore remain undiagnosed for years. Progressive weakness of the quadriceps muscles in sIBM is an early finding, followed by a decline in functional abilities, progressive loss of ambulation, and wheelchair dependence. The typical course of decline is 10–15 years after onset of the disease.3,4 Currently, no treatments have been found to slow or reverse the progression of muscle weakness and deterioration in sIBM.5–16 Recent opportunities for treatment of sIBM have emerged using strategies to inhibit the myostatin pathway to increase quadriceps muscle strength. Contrasting approaches include an inhibitory myostatin antibody that binds to the activin IIB receptor (BYM338; Novartis Pharmaceuticals; ClinicalTrials.gov) or an alternatively spliced product of the follistatin gene delivered by adeno-associated virus (AAV) directly into muscle.17,18 The quadriceps muscles are targets for these clinical trials because of their preferential weakness in sIBM, their suspected contribution to gait impairment, and their accessibility as a treatment target. In the BYM338 trial, the size of the quadriceps will be measured at 8 weeks and, in the follistatin gene therapy trial, quadriceps muscle strength is the intended primary outcome variable. Despite these laudatory goals, an important unaddressed issue is the absence of any previous study demonstrating a correlation between quadriceps muscle strength and function. In this study our aim was to directly assess knee extensor strength using the highest standards of measurement recognized by academic and regulatory authorities,19 including the 2- and 6-minute walk tests (2MWT and 6MWT)20; the IBM Functional Rating Scale (IBMFRS)21; and timed tests22–24 of stair climbing, standing from a chair, and stepping up on curbs.