Baumann Cory W, Lindsay Angus, Sidky Sylvia R, Ervasti James M, Warren Gordon L, Lowe Dawn A
Department of Biomedical Sciences, Ohio Musculoskeletal and Neurological Institute (OMNI), Ohio University, Athens, OH, United States.
Divisions of Rehabilitation Science and Physical Therapy, Department of Rehabilitation Medicine, University of Minnesota, Minneapolis, MN, United States.
Front Physiol. 2021 Oct 26;12:757121. doi: 10.3389/fphys.2021.757121. eCollection 2021.
Weakness and atrophy are key features of Duchenne muscular dystrophy (DMD). Dystrophin is one of the many proteins within the dystrophin glycoprotein complex (DGC) that maintains plasmalemmal integrity and cellular homeostasis. The dystrophin-deficient mouse is also predisposed to weakness, particularly when subjected to eccentric (ECC) contractions due to electrophysiological dysfunction of the plasmalemma. Here, we determined if maintenance of plasmalemmal excitability during and after a bout of ECC contractions is dependent on intact and functional DGCs rather than, solely, dystrophin expression. Wild-type (WT) and dystrophic mice (, mL172H and mimicking Duchenne, Becker and Limb-girdle Type 2E muscular dystrophies, respectively) with varying levels of dystrophin and DGC functionality performed 50 maximal ECC contractions with simultaneous torque and electromyographic measurements (M-wave root-mean-square, M-wave RMS). ECC contractions caused all mouse lines to lose torque (<0.001); however, deficits were greater in dystrophic mouse lines compared to WT mice (<0.001). Loss of ECC torque did not correspond to a reduction in M-wave RMS in WT mice (=0.080), while deficits in M-wave RMS exceeded 50% in all dystrophic mouse lines (≤0.007). Moreover, reductions in ECC torque and M-wave RMS were greater in mice compared to mL172H mice (≤0.042). No differences were observed between and mice (≥0.337). Regression analysis revealed ≥98% of the variance in ECC torque loss could be explained by the variance in M-wave RMS in dystrophic mouse lines (<0.001) but not within WT mice ( =0.211; =0.155). By comparing mouse lines that had varying amounts and functionality of dystrophin and other DGC proteins, we observed that (1) when all DGCs are intact, plasmalemmal action potential generation and conduction is maintained, (2) deficiency of the DGC protein β-sarcoglycan is as disruptive to plasmalemmal excitability as is dystrophin deficiency and, (3) some functionally intact DGCs are better than none. Our results highlight the significant role of the DGC plays in maintaining plasmalemmal excitability and that a collective synergism ( each DGC protein) is required for this complex to function properly during ECC contractions.
肌无力和萎缩是杜氏肌营养不良症（DMD）的关键特征。肌营养不良蛋白是肌营养不良蛋白糖蛋白复合体（DGC）中的众多蛋白质之一，该复合体维持质膜完整性和细胞稳态。缺乏肌营养不良蛋白的小鼠也易患肌无力，尤其是在经历离心（ECC）收缩时，这是由于质膜的电生理功能障碍所致。在此，我们确定了在一轮ECC收缩期间及之后质膜兴奋性的维持是否依赖于完整且功能正常的DGC，而非仅仅依赖于肌营养不良蛋白的表达。野生型（WT）小鼠和具有不同程度肌营养不良蛋白和DGC功能的营养不良小鼠（分别模拟杜氏、贝克和2E型肢带型肌营养不良症）进行50次最大ECC收缩，并同时测量扭矩和肌电图（M波均方根，M波RMS）。ECC收缩导致所有小鼠品系的扭矩降低（<0.001）；然而，与WT小鼠相比，营养不良小鼠品系的扭矩降低幅度更大（<0.001）。WT小鼠中ECC扭矩的降低与M波RMS的降低不相关（=0.080），而在所有营养不良小鼠品系中，M波RMS的降低幅度超过50%（≤0.007）。此外，与mL172H小鼠相比，小鼠中ECC扭矩和M波RMS的降低幅度更大（≤0.042）。与小鼠之间未观察到差异（≥0.337）。回归分析显示，在营养不良小鼠品系中（<0.001），ECC扭矩损失中≥98%的方差可由M波RMS的方差解释，但在WT小鼠中则不然（=0.211；=0.155）。通过比较具有不同数量和功能的肌营养不良蛋白及其他DGC蛋白的小鼠品系，我们观察到：（1）当所有DGC完整时，质膜动作电位的产生和传导得以维持；（2）DGC蛋白β-肌聚糖的缺乏对质膜兴奋性的破坏程度与肌营养不良蛋白缺乏时相同；（3）一些功能完整的DGC比没有DGC要好。我们的结果突出了DGC在维持质膜兴奋性方面的重要作用，并且该复合体在ECC收缩期间正常发挥功能需要集体协同作用（每个DGC蛋白）。
