Guo RY, Geng WC. Muscle-brain endocrine axis in autism spectrum disorder: Mechanisms, evidence, and research priorities. World J Psychiatry 2026; 16(10): 123438 [DOI: 10.5498/wjp.123438]
Corresponding Author of This Article
Rui-Yin Guo, Lecturer, Department of Basic Courses, Qilu Institute of Technology, No. 3028 Jingshi East Road, Jinan 250200, Shandong Province, China. guoruiin@163.com
Research Domain of This Article
Psychiatry
Article-Type of This Article
review-article
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Psychiatry. Oct 19, 2026; 16(10): 123438 Published online Oct 19, 2026. doi: 10.5498/wjp.123438
Muscle-brain endocrine axis in autism spectrum disorder: Mechanisms, evidence, and research priorities
Rui-Yin Guo, Wen-Cong Geng
Rui-Yin Guo, Department of Basic Courses, Qilu Institute of Technology, Jinan 250200, Shandong Province, China
Wen-Cong Geng, School of Marxism (Public Teaching Department), Linyi City Vocational College, Linyi 276017, Shandong Province, China
Author contributions: Guo RY conceptualized the review, designed the review framework, drafted the manuscript, and prepared the figures and tables; Geng WC contributed to the literature search, evidence organization, and critical revision of the manuscript. Both authors reviewed and approved the final version of the manuscript.
AI contribution statement: ChatGPT by OpenAI was used only for language editing, wording refinement, grammar checking, and editorial polishing. The tool was not used to generate scientific content, conduct literature analysis, prepare references, create figures or tables, perform data analysis, or conduct statistical analysis. All scientific interpretations, conclusions, and final manuscript decisions were reviewed and verified by the authors.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Rui-Yin Guo, Lecturer, Department of Basic Courses, Qilu Institute of Technology, No. 3028 Jingshi East Road, Jinan 250200, Shandong Province, China. guoruiin@163.com
Received: May 20, 2026 Revised: July 18, 2026 Accepted: August 20, 2026 Published online: October 19, 2026 Processing time: 144 Days and 5.4 Hours
Abstract
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition associated with alterations in synaptic plasticity, immune regulation, energy metabolism, and stress responsivity. Skeletal muscle is an endocrine organ that releases exercise-responsive mediators capable of participating in muscle-brain communication. This narrative review evaluates how irisin-related signaling, interleukin-6, brain-derived neurotrophic factor (BDNF)-related pathways, and metabolic mediators may intersect with four ASD-relevant domains: Synaptic plasticity, neuroinflammation, mitochondrial and energy metabolism, and hypothalamic-pituitary-adrenal axis regulation. ASD-specific mechanistic evidence remains limited. Gain- and loss-of-function studies in non-ASD models support the biological plausibility of several pathways, particularly FNDC5/irisin signaling, but do not establish causality in ASD. Human studies provide preliminary and heterogeneous evidence that exercise may alter peripheral biomarkers and selected behavioral or cognitive outcomes. The apparent BDNF paradox, elevated peripheral BDNF in some ASD cohorts despite the proposed benefits of exercise-related BDNF signaling, calls for compartment-, baseline-, and time-dependent interpretation. We therefore present the muscle-brain axis as a hypothesis-generating framework for future stratified trials rather than as a validated clinical prescription. Myokine profiling and pathway-targeted therapies should remain investigational pending the development of standardized assays, ASD-specific causal studies, and adequately powered randomized trials.
Core Tip: This review evaluates skeletal muscle-brain communication as a hypothesis-generating framework for autism spectrum disorder. It distinguishes autism-specific evidence from mechanistic findings derived from other disease models, addresses the brain-derived neurotrophic factor paradox, and emphasizes that the proposed links among irisin, interleukin-6, neuroplasticity, neuroinflammation, metabolism, and stress regulation vary substantially in evidential strength. Current data do not justify biomarker-guided exercise prescriptions or myokine-targeted therapy in clinical practice. Instead, the framework identifies testable mechanisms, major translational gaps, and priorities for stratified randomized trials.
