Duchenne muscular dystrophy (DMD) is the most common form of progressive childhood muscular dystrophy associated with weakness of limbs, loss of ambulation, heart weakness and early death. The mutations causing either loss-of-expression or function of the full-length protein dystrophin (Dp427) from the DMD gene are responsible for the disease pathology. Dp427 forms a part of the large dystroglycan complex, called DAPC, in the sarcolemma, and its absence derails muscle contraction. Muscle biopsies from DMD patients show an overactivation of excitation-contraction-coupling (ECC) activable calcium incursion, sarcolemmal ROS production, NHE1 activation, IL6 secretion, etc. The signalling pathways, like Akt/PBK, STAT3, p38MAPK, and ERK1/2, are also hyperactive in DMD. These pathways are responsible for post-mitotic trophic growth and metabolic adaptation, in response to exercise in healthy muscles, but cause atrophy and cell death in dystrophic muscles. We hypothesize that the metabolic background of repressed glycolysis in DMD, as opposed to excess glycolysis seen in cancers or healthy contracting muscles, changes the outcome of these ‘growth pathways’. The reduced glycolysis has been considered a secondary outcome of the cytoskeletal disruptions seen in DMD. Given the cytoskeleton-crosslinking ability of the glycolytic enzymes, we hypothesize that the failure of glycogenolytic and glycolytic enzymes to congregate is the primary pathology, which then affects the subsarcolemmal cytoskeletal organization in costameres and initiates the pathophysiology associated with DMD, giving rise to the tissue-specific differences in disease progression between muscle, heart and brain. The lacunae in the regulation of the key components of the hypothesized metabolome, and the limitations of this theory are deliberated. The considerations for developing future therapies based on known pathological processes are also discussed.

杜氏肌营养不良症 (DMD) 是最常见的进行性儿童肌营养不良症，与四肢无力、无法行走、心脏无力和早逝有关。导致DMD中全长抗肌萎缩蛋白 (Dp427) 表达缺失或功能缺失的突变基因负责疾病病理学。Dp427 是肌膜中称为 DAPC 的大肌营养不良聚糖复合体的一部分，它的缺失会破坏肌肉收缩。DMD 患者的肌肉活检显示兴奋-收缩-偶联 (ECC) 可激活钙侵入、肌膜 ROS 产生、NHE1 激活、IL6 分泌等过度激活。信号通路，如 Akt/PBK、STAT3、p38MAPK 和 ERK1/2 , 在 DMD 中也过度活跃。这些途径负责有丝分裂后的营养生长和代谢适应，以响应健康肌肉的运动，但会导致营养不良的肌肉萎缩和细胞死亡。我们假设 DMD 中抑制糖酵解的代谢背景，与癌症或健康收缩肌肉中看到的过度糖酵解相反，改变了这些“生长途径”的结果。糖酵解减少被认为是 DMD 中细胞骨架破坏的次要结果。鉴于糖酵解酶的细胞骨架交联能力，我们假设糖原分解和糖酵解酶无法聚集是主要病理学，然后影响肋节中的肌膜下细胞骨架组织并启动与 DMD 相关的病理生理学，从而产生组织-肌肉、心脏和大脑之间疾病进展的特定差异。对假设的代谢组关键成分的调控存在缺陷，并讨论了该理论的局限性。还讨论了基于已知病理过程开发未来疗法的注意事项。