From exercise-associated lactate to the tubulin code: α-tubulin lactylation as a candidate mechanism for poststroke neural remodeling
Year: 2026
Type: article
Abstract: Aerobic exercise promotes functional recovery after ischemic stroke, but the proposed link between an exercise-associated lactate pulse and durable neural remodeling remains unproven. The metabolite relevant to the hypothesis is L-lactate generated by skeletal-muscle glycolysis. In the principal mouse study, moderate treadmill exercise begun on poststroke day 6 (10 m/min, 30 min/day for 14 days) increased circulating and brain lactate together with α-tubulin lysine 40 (K40) lactylation and recovery; this regimen cannot be assumed feasible in patients with acute or severe disability. Electrically evoked skeletal-muscle contraction offers a preclinical exercise-mimetic option for nonambulatory subjects and increased circulating lactate in stroke mice, but it has not established a therapeutic lactate target, brain K40 lactylation, or clinical efficacy. Mechanistically, concurrent changes in L-lactate, K40 lactylation, and recovery show association rather than causal mediation. Exogenous L-lactate and dichloroacetate broadly alter metabolism and signaling, while substrate oxidation, HCAR1/VEGF signaling, BDNF/NMDAR-related plasticity, and lactylation of other proteins remain parallel explanations. The in vivo role of K40 lactylation has not been tested by a selective blockade. Moreover, the LacAVC phase IIa intravenous lactate trial was terminated after 28 enrollments for recruitment and protocol-related reasons. Although no results have been posted in the trial registry, a 2026 conference abstract reported preliminary safety and cerebral-bioavailability findings without establishing clinical efficacy or α-tubulin K40 target engagement.
Source: Frontiers in Physiology
Authors: Jing Guo, Hongxiao Wang
Institution: Hanshan Normal University
Language: English
Subfield: Rehabilitation
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
Funder: Hanshan Normal University
OpenAlex ID: W7224113580