A Natural History Study of Hindlimb Physiology and Histopathology in a Heterozygous OPMD Mouse Model

Background

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset autosomal dominant myopathy. OPMD is caused by a short alanine expansion in the gene encoding for poly(A) binding protein nuclear 1 (PABPN1) forming insoluble nuclear aggregates. OPMD patients are predominantly heterozygous, and the knock-in Pabpn1^+/A17 mouse, which expresses one copy of the expanded Pabpn1 gene under the PABPN1 promoter genetically, mimics OPMD. Insights into the A17/+ mouse model are necessary to evaluate its preclinical value and test therapeutics for OPMD. Here, we performed a natural disease history study for the A17/+ model.

Methods

We combined muscle force measurements of the tibialis anterior with magnetic resonance imaging (MRI) measurements of the calf muscles made in 4-, 8- and 12-month-old wild-type and A17/+ mice. These measures were complemented by muscle histopathology staining and image quantification to detect PABPN1 aggregates and to assess muscle wasting. Statistical significance between genotypes over the three time points was assessed using ANOVA or Student's t test.

Results

PABPN1 nuclear aggregates were found in the 12-month-old A17/+ mice at similar quantities of ~2% across hindlimb muscles. We did not observe changes in muscle strength of the tibialis anterior in A17/+ mice. MRI analyses of hindlimb muscles revealed no metabolic difference, no fatty infiltration and limited muscle atrophy between A17/+ and +/+ mice. The plantaris muscle in A17/+ showed 30% atrophy at 12 months of age, which was corroborated by a 30% myofiber shift in the myosin heavy chain −2A to −2B ratio. Histopathologic staining did not reveal muscle wasting in the hindlimb muscles.

Conclusions

Despite the presence of PABPN1 insoluble aggregates in hindlimb muscles, muscle involvement in the 12-month-old A17/+ mice was limited. Our results query the usefulness of A17/+ hindlimb muscles for preclinical studies.