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

Table 1 Evidence map and translational gaps across proposed muscle-brain mechanisms in autism spectrum disorder

Mechanistic domain	ASD-specific evidence	Transdiagnostic mechanistic evidence	Human/clinical evidence	Typical methods represented	Current interpretation and key translational gap	Ref.
Synaptic plasticity and BDNF/TrkB signaling	Altered synaptic structure and function are reported in ASD-relevant models and subgroups. Peripheral BDNF findings are heterogeneous; MDGA2 deficiency can produce excessive BDNF/TrkB activation and autism-relevant phenotypes in mice. An ASD exercise trial reported concurrent serum BDNF and executive-function changes	Exercise-related PGC-1α/FNDC5/irisin signaling can influence hippocampal BDNF-associated pathways in non-ASD systems. Mechanistic studies also show that precursor and mature BDNF can engage distinct signaling programs	Peripheral BDNF differs between some ASD and comparison cohorts, but serum/plasma measures are strongly influenced by platelet storage and release and by pre-analytical handling. Parallel changes in biomarkers and behavior do not establish mediation	Genetic and pathway-manipulation models; systematic review/meta-analysis; peripheral biomarker assays; exercise intervention trial	Biological plausibility is substantial, but ASD-specific causal mediation remains unproven. The BDNF paradox requires baseline-, compartment-, time-, and molecular-form-specific testing; peripheral BDNF should remain an exploratory marker of response	[3,11,55-65]
Neuroinflammation and microglial states	Innate immune dysfunction, neuroinflammation, and altered microglial programs have been implicated in subsets of ASD. Causal role, developmental timing, and subgroup specificity remain unresolved	Exercise-related IL-6 responses are context dependent. Human experimental studies show that IL-6 can increase IL-1ra/IL-10 and that exercise or IL-6 infusion can attenuate endotoxin-induced TNF-α. Single-cell studies demonstrate multidimensional microglial heterogeneity beyond a binary M1/M2 model	There is no direct demonstration that exercise-induced, muscle-derived IL-6 crosses the blood-brain barrier and reprograms human microglia in ASD. Clinical ASD evidence is therefore indirect	ASD neuroimmune reviews; human cytokine infusion/exercise experiments; single-cell transcriptomics; observational immune profiling	The pathway is best treated as an indirect, hypothesis-level model. A demonstrated M1-to-M2 conversion should not be inferred. ASD studies need time-resolved peripheral mediator measures linked to central neuroimmune readouts and functional outcomes	[4,12,66-70]
Energy metabolism, mitochondrial dysfunction, and lactate	Mitochondrial abnormalities and mitochondrial-dysfunction biomarkers have been reported in ASD subsets, with substantial biological heterogeneity. A single cerebral-energy-deficit model should not be generalized across the spectrum	Exercise improves insulin signaling and systemic glucose regulation. Lactate acts as a metabolic substrate and signaling molecule; the human brain can increase lactate uptake during exercise. Sustained oxidative use of lactate depends on downstream mitochondrial capacity	Direct human evidence that exercise-derived lactate corrects ASD-associated mitochondrial dysfunction or mediates behavioral improvement is insufficient	Systematic reviews/meta-analyses; metabolic physiology; brain substrate-uptake studies; mechanistic and integrative reviews	Metabolic support is plausible, but lactate is not a myokine and should not be presented as a generic bypass for mitochondrial dysfunction. ASD-specific mediation requires metabolic phenotyping linked to brain measures and outcomes	[5,13,71-79]
HPA axis and stress response	Meta-analytic and review evidence indicates altered cortisol patterns and stress responsivity in ASD, but findings vary by developmental stage, sampling method, stress paradigm, and subgroup. Exercise studies report selected improvements in emotional and behavioral outcomes	In broader populations, higher physical activity is associated with a steeper diurnal cortisol slope, although effects are not uniform across HPA indices. IL-6- and irisin-related immune/neurotrophic pathways provide only indirect links to stress-regulatory systems	No direct evidence establishes that a specific muscle-derived myokine recalibrates HPA-axis function in ASD. Behavioral change can arise through multiple nonexclusive mechanisms	Cortisol meta-analysis; stress-system review; physical-activity meta-analysis; ASD behavioral intervention studies	The muscle-HPA link is a testable indirect hypothesis, not an established mechanism. Future trials require repeated cortisol sampling, standardized stress tasks, mediator kinetics, and formal mediation analyses	[6,53,54,60,68,80-82]
Cross-cutting biomarkers and stratified exercise translation	ASD exercise outcomes are heterogeneous. Broad symptom severity and stereotyped behaviors show null or inconsistent effects in some syntheses. Peripheral BDNF and irisin profiles vary across cohorts, and an aquatic-exercise trial showed concurrent, but not necessarily mediated, changes in BDNF and executive function	Exercise-responsive BDNF, IL-6, and irisin vary with intervention characteristics, participant characteristics, sampling conditions, and assay methodology. Multiple non-muscle factors influence circulating BDNF levels; human irisin studies show methodological heterogeneity	No validated ASD-specific biomarker thresholds, response-prediction rules, or genotype- or omics-based exercise decision algorithms currently exist. Pediatric BDNF RCT evidence is not uniformly positive and is not ASD-specific	Clinical-trial syntheses; systematic reviews/meta-analyses; biomarker studies; exercise RCTs; assay-methodology reviews	Myokines and related mediators should be treated as candidate research measures, not validated clinical biomarkers. Priorities include assay standardization, prespecified subgroup analyses, mediation testing, external validation, and comparison with standard clinical assessment	[6,12,44,45,57,59,62-64,86-90,97,98,102]

Evidence categories reflect study context and narrative interpretation, not formal risk-of-bias grading.

ASD: Autism spectrum disorder; BDNF: Brain-derived neurotrophic factor; TrkB: Tropomyosin receptor kinase B; PGC-1α: Peroxisome proliferator-activated receptor γ coactivator-1α; FNDC5: Fibronectin type III domain-containing protein 5; IL: Interleukin; TNF-α: Tumor necrosis factor-α; HPA: Hypothalamic-pituitary-adrenal; RCT: Randomized controlled trial.