Table 1.

Overview of muscle-derived and exercise-induced endocrine signals involved in the periphery-brain crosstalk.

Protein or metabolite	Tissue	Experimental models	Detected in blood	Transport/receptor	Central effects	Main references
IDENTIFIED AND PUTATIVE MUSCLE-DERIVED FACTORS TRIGGERED BY EXERCISE
Cathepsin B	Skeletal muscle	CTSB KO mice Rat myotubes + AICAR treatment Peripheral CTSB injection	Human Rhesus Monkey Mouse	BBB crossing/ ?	↑ Hippocampal neurogenesis + spatial memory ↑ Hippocampal BDNF + DCX	(114)
Irisin	Brain Skeletal muscle	PGC-1α KO mice Adenovirus-mediated overexpression of PGC-1α (neurons) and FNDC5 (liver)	Human Mouse	BBB crossing/ ?	↑ Hippocampal BDNF	(89)
L-Lactate	Skeletal muscle	HCAR1 KO mice Exogenous L-lactate injection	Human Mouse	MCTs/HCAR1 at the BBB	↑ Vascularization ↑ VEGFA expression and vascularization	(115)
?	Skeletal muscle	Peripheral AICAR injection Deletion of the AMPK α2-subunit in mouse muscle	?	?	↑ Hippocampal neurogenesis + spatial memory	(58, 59)
Protein or metabolite	Tissue/stimulus	Experimental models	Detected in blood	Transport/receptor	Central effects	Main references
ADDITIONAL FACTORS (NOT NECESSARILY INDUCED BY PHYSICAL ACTIVITY OR DERIVED FROM SKELETAL MUSCLE)
β-hydroxybutyrate	Liver (fasting + PA)	Exercise mouse Central β-hydroxybutyrate injection shRNA-mediated KD of HDAC3	Human Mouse	MCTs and HCARs at the BBB	↓ HDAC2 and HDAC3 recruitment at Bdnf promoters ↑ Hippocampal BDNF ↑ Glutamate release	(116)
Fibroblast growth factor 21	Liver (PA) Adipose Skeletal muscle	Peripheral and central FGF21 injection Overexpression of FGF21 in mouse liver Deletion of β-Klotho in mouse brain	Human Mouse	BBB crossing/βKlotho, FGFR1	Regulation of metabolism, energy expenditure, and circadian behavior	(117–119)
Insulin-like growth factor-1	Liver (PA)	Exercise rat Peripheral IGF-1 injection Anti-IGF-1 antibody + IGF-1 receptor antagonist	Human Rat Mouse	BBB crossing/IGF-1 receptor at the BBB	↑ Hippocampal neurogenesis and BDNF expression	(86, 87, 120)
Kynurenin (KYN) Kynurenic acid (KYNA)	Liver Skeletal muscle (PA)	Exercise mouse Overexpression/deletion of PGC-1α in mouse muscle Peripheral KYN injection	Human Mouse	KYN can cross the BBB but not KYNA/ ?	↓ KYN accumulation decreases stress-induced neurobiological mechanisms of depression	(121, 122)
?	Skeletal muscle	Mouse global, brain- or muscle-specific deletion/overexpression of BMAL1	?	?	Regulation of NREM sleep time and sleep recovery following sleep deprivation	(123)

BBB, blood-brain barrier; PA, physical activity.