Lactate As A Signaling MoleculeEdit
Lactate, long viewed as merely a byproduct of muscle activity, has emerged in recent decades as a versatile signaling molecule that coordinates metabolism, gene expression, and tissue adaptation. Its production rises whenever cells run glycolysis hard, but its influence extends far beyond simple energy supply. Across tissues such as skeletal muscle, heart, brain, and tumor microenvironments, lactate acts through transporters, receptors, and epigenetic marks to convey information about the organism’s energetic state and to mold cellular responses. This shift in understanding has reshaped how scientists think about exercise physiology, neurobiology, cancer biology, and metabolic regulation.
The story of lactate as a signaling cue intersects with a broader narrative about how metabolism communicates with cellular programs. Early views framed lactate as a waste product to be cleared; today, researchers emphasize a bidirectional lactate shuttle in which lactate is both a fuel and a signal. The mechanisms are diverse and context dependent, incorporating membrane transport, receptor signaling, and metabolism-linked chromatin modifications. As with many emerging areas, there are important debates about how universal and physiologically meaningful certain signaling roles are, how they vary between tissues, and how best to interpret measurements made in plasma versus inside cells.
Mechanisms of signaling
Transport and compartmentalization
Lactate moves between cells mainly via monocarboxylate transporters (MCTs). In glycolytically active tissues, MCT4 tends to export lactate; in oxidative tissues, MCT1 supports import for oxidation or further metabolism. Once inside a cell, lactate can be converted back to pyruvate and funneled into the mitochondria, contributing to ATP production or feeding the TCA cycle. This shuttling supports the view of lactate as a currency of metabolic exchange, linking producer and consumer tissues in a coordinated network. See monocarboxylate transporter for background on transporter biology and distribution across tissues.
Receptor-mediated signaling
Lactate can act as a ligand for G-protein–coupled receptors, notably GPR81 (also known as HCAR1). Activation of this receptor can reduce cyclic AMP in certain cell types, influencing metabolic processes such as lipolysis in adipose tissue. The extent of GPR81’s role across different tissues and physiological states remains an area of active investigation, but receptor-mediated signaling provides a direct mechanism by which extracellular lactate can influence cellular behavior beyond substrate supply. See GPR81 for a more detailed discussion of this receptor.
Epigenetic and transcriptional regulation
A striking area of lactate signaling involves epigenetic modifications. Histone lysine lactylation—a chemical mark added to histone proteins in response to intracellular lactate levels—links glycolytic flux to gene regulation. This modification has been observed in particular immune cells and during certain activation states, suggesting that metabolic state can shape transcriptional programs via histone chemistry. The prevalence and functional importance of histone lactylation across tissues and physiological conditions is still being clarified, with some studies showing clear associations with gene expression while others stress context dependence and the need for stronger causal evidence. See histone lactylation for more on this promising but evolving field.
Metabolic and developmental signaling
Beyond histone lactylation, lactate influences transcription and signaling pathways related to hypoxia signaling, mitochondrial biogenesis, and angiogenesis. For example, lactate can stabilize or perturb factors that regulate vascular growth and energy metabolism, contributing to adaptive responses in muscle, brain, and tumors. The lasting impact of these signals often depends on the cellular context, the availability of receptors, and the balance with other metabolic cues. See VEGF and PGC-1alpha for related pathways influenced by metabolic state.
Physiological contexts and implications
Exercise physiology
During intense or prolonged exercise, plasma and tissue lactate rise markedly. Rather than simply pooling as a waste product, lactate serves as a substrate for oxidative tissues and as a signaling molecule that promotes adaptations such as increased mitochondrial content and angiogenesis. The lactate shuttle concept—a driver of this perspective—posits coordinated lactate production and utilization among muscles and other organs, supporting sustained performance and recovery. See exercise physiology for a broader view of exercise-related metabolic signaling.
Brain and nervous system
The brain can utilize lactate as an energetic substrate, particularly under stress or high activity. Lactate signaling may influence neuronal metabolism and plasticity, and ongoing research explores its role in learning, memory, and neuroprotection. The precise balance between lactate as fuel and lactate as a signal in neural tissue remains an area of active inquiry, with implications for how the brain links energy status to function. See neuroscience and lactate for adjacent topics.
Immune system and inflammation
In immune cells, metabolic cues can shape responses, and lactate has emerged as a modulator of polarization and activity in certain contexts. Through both receptor-mediated and epigenetic mechanisms, lactate may help tune the inflammatory state, potentially affecting how the immune system responds to infections or tissue injury. See macrophage polarization for related immunometabolic concepts.
Cancer metabolism
Tumor cells and their microenvironment often exhibit altered glycolysis, producing substantial lactate. In many cancers, lactate acts as a signaling molecule that can promote angiogenesis, immune evasion, and metabolic reprogramming, reinforcing tumor growth. This has spurred interest in targeting lactate production, transport, or signaling as a therapeutic strategy, though such approaches must navigate potential effects on normal tissues and systemic metabolism. See cancer metabolism for a broader treatment landscape.
Controversies and debates
Lactic signaling versus metabolic fuel: A central debate concerns the relative importance of lactate as a fuel compared with its signaling roles. While it clearly serves as an energy source under certain conditions, many of the signaling effects appear to be independent of fuel provision and depend on transport, receptors, or epigenetic modifications. The consensus emphasizes a dual role, with the balance shifting by tissue, state, and context. See glycolysis and mitochondrial biogenesis for related concepts.
The lactate shuttle and its limits: The idea that lactate is rapidly shuttled between cells to oxidize in distant tissues has strong supporters and critics. Proponents highlight transporter distribution and in vivo measurements that align with intercellular lactate exchange; skeptics point to measurement challenges and tissue-specific variation that complicate universal claims. See lactate shuttle for an overview of this debate.
Histone lactylation: The discovery of histone lactylation opened a new channel for linking metabolism to gene regulation, but the field faces questions about causality, scope, and functional relevance across tissues and physiological states. Some findings point to robust regulatory roles under certain conditions, while others urge caution in extrapolating from specific models. See histone lactylation for a synthesis of current evidence and ongoing work.
Receptor biology and in vivo relevance: GPR81/HCAR1 is a credible lactate receptor in several contexts, but translating in vitro receptor activity to in vivo physiology remains challenging. Differences in receptor expression across tissues, subtypes, and developmental stages mean that lactate signaling cannot be assumed uniform across the organism. See GPR81 for receptor-focused discussion and current evidence.
Therapeutic targeting and safety: Approaches designed to disrupt lactate production, transport, or signaling to treat cancer or metabolic disease must consider potential adverse effects on normal tissues that rely on lactate signaling for homeostasis, energy supply, and adaptation to stress. This remains a key hurdle in translating mechanistic insights into safe therapies. See therapeutics and cancer therapy for related considerations.