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

Table 2 Autism spectrum disorder-specific intervention evidence and transdiagnostic mechanistic evidence relevant to the proposed muscle-brain axis

Evidence tier	Model/population	Intervention/manipulation	Main findings	Relevance to the proposed muscle-brain axis and major limitation	Ref.
ASD-specific exercise evidence	BTBR mice (ASD-relevant model)	5 weeks of voluntary wheel running	Attenuated nociceptive abnormalities; no significant improvement in social interaction deficits	Shows outcome-specific effects of physical activity in an ASD-relevant model. Does not establish myokine mediation or broad behavioral efficacy	[83]
ASD-specific multimodal contextual evidence	Juvenile BTBR mice	Semi-natural housing/environmental enrichment with social and physical components	Improved social behavior and reduced repetitive exploratory behavior	Relevant to multimodal interventions, but not an isolated exercise manipulation; effects cannot be attributed specifically to physical activity	[84]
ASD-specific exercise evidence	Male and female rats with VPA-induced autism-like phenotype	Low- and moderate-intensity interval training	Improved selected anxiety-like and social outcomes; spatial learning and memory did not significantly improve	Supports outcome-specific rather than uniform efficacy. Myokine mediation was not demonstrated	[85]
ASD-specific clinical intervention evidence	Children with ASD	Aquatic exercise intervention	Improved selected executive-function outcomes; serum BDNF increased concurrently	Provides preliminary concurrent human evidence. Co-occurrence does not establish BDNF mediation, skeletal muscle origin, or central target engagement	[62]
ASD-specific clinical synthesis	Autistic children, adolescents, and broader autistic samples across exercise trials	Multiple exercise modalities	Syntheses report benefits for selected social, cognitive, sleep, anxiety, and functional outcomes, but effects are heterogeneous, and some domains show null or inconsistent results	Supports continued clinical investigation while arguing against broad efficacy claims or inference of a single biological mechanism	[6,87-88,102]
ASD-specific mechanistic synthesis	Autistic individuals/ASD-relevant literature	Mechanistic review of exercise interventions	Summarizes candidate neuronal, glial, and gut microbiota-related pathways	Useful for hypothesis generation; mechanistic review evidence does not demonstrate direct causal mediation by myokines	[89,103]
ASD-specific biomarker evidence	Children with ASD	Cross-sectional serum BDNF assessment	Elevated or altered peripheral BDNF has been reported; some studies associate higher levels with symptom severity	Central to the BDNF paradox: Higher peripheral BDNF is not equivalent to beneficial central signaling. Cross-sectional data cannot establish cause, compensation, or tissue source	[57,59]
ASD-specific biomarker evidence	Children with ASD vs healthy controls	Cross-sectional serum irisin assessment	Lower circulating irisin was reported in ASD	Suggests a potential association with physical inactivity or metabolic phenotype but does not establish a causal deficiency or muscle-to-brain mediation	[86]
ASD-specific synaptic mechanism	Mdga2-deficient mice with autism-relevant phenotype	Genetic disruption of a synaptic regulator	Aberrant/excessive BDNF-TrkB signaling was linked to synaptic and autism-relevant behavioral changes	Demonstrates that greater TrkB signaling is not uniformly beneficial and supports caution regarding BDNF/TrkB-targeted strategies. This was not an exercise study	[58]
Transdiagnostic foundational mechanism	Non-ASD mice	Exercise-induced PGC-1α/FNDC5 pathway activation	Exercise-induced hippocampal BDNF through a PGC-1α/FNDC5-related pathway	Provides foundational biological plausibility for an exercise-responsive FNDC5/BDNF pathway. Does not establish ASD-specific mediation	[11]
Transdiagnostic mechanistic evidence	Non-ASD mice; Alzheimer’s disease model	Whole-body FNDC5 loss of function; experimental elevation of circulating irisin	Loss of FNDC5 abolished selected exercise-related cognitive effects; elevated circulating irisin improved selected cognitive and neuropathological outcomes in an Alzheimer’s disease model	Supports pathway dependence or sufficiency within those models. Neurodegenerative findings cannot be treated as causal evidence in ASD	[42]
Transdiagnostic peripheral mechanism	Aging-associated sarcopenia mouse model	Muscle-specific FNDC5 deletion during aerobic exercise	Deletion impaired exercise-related benefits in muscle function and mass	Supports a role for muscle-derived FNDC5/irisin in peripheral exercise adaptation. Does not establish brain or ASD mediation	[50]
Transdiagnostic mechanistic evidence	Non-ASD mouse model	Irisin-neutralizing antibody during exercise	Attenuated selected cognitive and mood-related effects and reduced exercise-associated hippocampal BDNF upregulation and cell proliferation	Supports pathway dependence in a non-ASD setting. Generalization to ASD requires direct validation	[51]
Transdiagnostic molecular mimicry evidence	Non-ASD experimental context; quadriceps muscle	Recombinant irisin administration	Induced skeletal muscle proteomic, metabolic, and microstructural changes resembling aspects of exercise adaptation	Supports partial molecular mimicry in muscle. Does not demonstrate CNS effects, behavioral benefits, or ASD relevance on its own	[52]
Non-ASD pediatric biomarker synthesis	Children aged 5-12 years across randomized exercise trials; not restricted to ASD	Exercise interventions with peripheral BDNF measurement	Only two of five included randomized trials reported significant exercise-related increases in BDNF	Demonstrates that BDNF responses are not uniformly positive even in pediatric exercise studies. Not ASD-specific and cannot establish mediation	[90]

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

ASD: Autism spectrum disorder; VPA: Valproic acid; 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; CNS: Central nervous system.