Impaired muscle proprioceptor function in an Angelman Syndrome mouse model

Angelman syndrome (AS) is a neurodevelopmental disorder that is caused by maternal loss of function of the E3 Ubiquitin-protein ligase UBE3A. AS leads to developmental delays and abnormal coordination, balance, and gait. Recent studies have demonstrated that maternal but not paternal loss of Ube3A leads to reduced Piezo2 channel activity in dorsal root ganglion sensory neurons and gait abnormalities in mice. Previous work from our lab has shown that Piezo2 is necessary for muscle spindle (MS) afferent function. Therefore the objective of our study is to determine whether this decrease in Piezo2 channel activity alters mechanosensation in the MS afferent using an AS mouse model. We hypothesize that AS mice will have altered proprioceptor function and gait abnormalities compared to mice with normal Ube3a expression. Male and female mice 2-3 months old with maternal loss of Ube3a (Ube3am-/p+ AS, n=12) or paternal loss of Ube3a (Ube3am+/p- CON, n=12) were challenged on a ladder walking assay then manually scored for total steps and missteps. One week after behavioral testing the extensor digitorum longus and sciatic nerve were placed in an ex vivo bath with oxygenated synthetic interstitial fluid at 24°C. To evaluate stretch sensitivity the muscle was held at the length that produced maximal force of twitch contraction (Lo) and given a series of 9 ramp-and-hold stretches (4s long, 2.5, 5, and 7.5% of Lo repeated 3 times each). To determine muscle fatigability a low frequency fatigue protocol was administered (300 ms trains, 60Hz frequency, 0.5 ms pulse width, every 3 seconds for 6 minutes). AS mice weighed more than controls (25.30g ±3.56 vs 21.78g ±3.78, p< 0.05) as reported in previous studies. EDL muscle cross sectional area (1.13 mg/mm ± 0.41 vs 1.17 mg/mm ±0.30, p=0.78) and fatigability were not significantly different between groups (-84.95% ±4.94 vs -86.77% ± 6.78, p=0.58), suggesting no large changes in muscle contractile properties. However, AS afferents had an impaired ability to fire throughout the entirety of the stretch and more variable firing rates than CON afferents. A higher percentage of CON mice had at least 1 afferent that fired throughout stretch at all three stretch lengths compared to AS mice (2.5% Lo - AS 50% vs CON 70%, χ 2 (1) = 8.33, p =0.004; 5% Lo - 50% vs 80%,χ 2 (1) = 19.78 p< 0.001; 7.5% Lo - 60% vs 80%,χ 2 (1) = 9.52 p= 0.002; n=10/group). This suggests decreased MS afferent static stretch sensitivity presumably due to decreased Piezo2 channel activity. While others have reported gait abnormalities including longer stride length in AS mice, we did not see an increased rate of missteps on the ladder walking assay (AS 2.50 ± 2.39 vs CON 1.583 ± 0.996, p = 0.24). Future work will determine whether younger AS mice (P7-11) have similar MS afferent deficits or if compensation over development occurs. Findings from this study will help elucidate how altered Piezo2 channel activity, which occurs in multiple neuromuscular diseases, can impact the fidelity of muscle proprioceptor sensory activity and sensorimotor function. This project was funded by NIH R16GM153600 (KAW) and T33GM149461 (FAB). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.