Muscle-brain endocrine axis in autism spectrum disorder: Mechanisms, evidence, and research priorities

Figure 1 Intersections between major autism spectrum disorder pathophysiological domains and myokine signaling. Proposed intersections between exercise-responsive peripheral mediators and autism spectrum disorder-relevant pathophysiological domains. Solid arrows denote relatively well-supported associations, dashed arrows denote indirect links, and dotted arrows denote hypothesis-level relationships requiring autism-specific causal validation. Candidate pathways include brain-derived neurotrophic factor/tropomyosin receptor kinase B-related plasticity, neuroimmune signaling, lactate transport and metabolism, and hypothalamic-pituitary-adrenal-axis regulation. The figure should not be interpreted as evidence that muscle-derived interleukin-6 directly crosses the blood-brain barrier or causes a binary M1-to-M2 microglial switch in autism spectrum disorder. MR: Mineralocorticoid receptor; AMPK: AMP-activated protein kinase; PGC-1α: Peroxisome proliferator-activated receptor γ coactivator-1α; FNDC5: Fibronectin type III domain-containing protein 5; IL: Interleukin; MCT: Monocarboxylate transporter; ASD: Autism spectrum disorder; TrkB: Tropomyosin receptor kinase B; HPA: Hypothalamic-pituitary-adrenal; ANLS: Astrocyte-neuron lactate shuttle.

Figure 2 Hypothesis-generating translational framework for staged exercise research in autism spectrum disorder. Phase 1 distinguishes currently feasible clinical and behavioral inputs from emerging or research-only stratification measures. Phase 2 depicts proposed exercise-responsive muscle and systemic pathways, with biomarkers labeled as candidate research measures and recombinant or small-molecule approaches as investigational targets. Phase 3 shows potential combinations with behavioral therapy, neuromodulation, and pharmacotherapy; direct synergistic efficacy remains to be established. IL: Interleukin; BDNF: Brain-derived neurotrophic factor; TrkB: Tropomyosin receptor kinase B; PGC-1α: Peroxisome proliferator-activated receptor γ coactivator-1α; HPA: Hypothalamic-pituitary-adrenal; ABA: Applied behavior analysis; CBT: Cognitive behavioral therapy; PMC: Premotor cortex; HPC: Hippocampus; PFC: Prefrontal cortex; FNDC5: Fibronectin type III domain-containing protein 5; STAT3: Signal transducer and activator of transcription 3; AMPK: AMP-activated protein kinase; MCTs: Monocarboxylate transporters; Akt: Protein kinase B; IGF-1: Insulin-like growth factor 1; PI3K: Phosphoinositide 3-kinase; CRH: Corticotropin-releasing hormone; ACTH: Adrenocorticotropic hormone; rTMS: Repetitive transcranial magnetic stimulation; tDCS: Transcranial direct current stimulation.