Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.
University of Iowa, Iowa City, Iowa, USA.
JCI Insight. 2023 Nov 22;8(22):e171772. doi: 10.1172/jci.insight.171772.
Aging and many illnesses and injuries impair skeletal muscle mass and function, but the molecular mechanisms are not well understood. To better understand the mechanisms, we generated and studied transgenic mice with skeletal muscle-specific expression of growth arrest and DNA damage inducible α (GADD45A), a signaling protein whose expression in skeletal muscle rises during aging and a wide range of illnesses and injuries. We found that GADD45A induced several cellular changes that are characteristic of skeletal muscle atrophy, including a reduction in skeletal muscle mitochondria and oxidative capacity, selective atrophy of glycolytic muscle fibers, and paradoxical expression of oxidative myosin heavy chains despite mitochondrial loss. These cellular changes were at least partly mediated by MAP kinase kinase kinase 4, a protein kinase that is directly activated by GADD45A. By inducing these changes, GADD45A decreased the mass of muscles that are enriched in glycolytic fibers, and it impaired strength, specific force, and endurance exercise capacity. Furthermore, as predicted by data from mouse models, we found that GADD45A expression in skeletal muscle was associated with muscle weakness in humans. Collectively, these findings identify GADD45A as a mediator of mitochondrial loss, atrophy, and weakness in mouse skeletal muscle and a potential target for muscle weakness in humans.
衰老是许多疾病和损伤的共同后果，会导致骨骼肌质量和功能下降，但其中的分子机制尚未完全阐明。为了更好地理解这些机制，我们构建并研究了一种转基因小鼠，该小鼠在骨骼肌中特异性表达生长停滞和 DNA 损伤诱导蛋白 45α（GADD45A）。在衰老和多种疾病及损伤过程中，GADD45A 在骨骼肌中的表达水平会升高。我们发现，GADD45A 诱导了几种与骨骼肌萎缩相关的细胞变化，包括骨骼肌线粒体和氧化能力减少、糖酵解型肌纤维选择性萎缩以及尽管存在线粒体丧失但仍出现氧化型肌球蛋白重链的反常表达。这些细胞变化至少部分是由丝裂原活化蛋白激酶激酶激酶 4 介导的，该蛋白激酶可被 GADD45A 直接激活。通过诱导这些变化，GADD45A 降低了富含糖酵解型纤维的肌肉质量，并损害了肌肉力量、比肌力和耐力运动能力。此外，正如来自小鼠模型的数据所预测的那样，我们发现 GADD45A 在骨骼肌中的表达与人类的肌肉无力有关。总之，这些发现表明 GADD45A 是小鼠骨骼肌中线粒体丧失、萎缩和无力的介导物，也是人类肌肉无力的潜在靶点。
