Lactate as a major myokine and exerkine

Brooks, George A.; Osmond, Adam; Arevalo, José A.; Curl, Casey C.; Duong, Justin J.; Horning, Michael A.; Santillan, Diana D. Moreno; Leija, Robert G.

doi:10.1038/s41574-022-00724-0

Cited by 22 publications

(12 citation statements)

References 10 publications

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“…Mechanisms by which lactate operates to control energy substrate partitioning include mass action ( 3 ), allosteric binding ( 23 , 24 , 248 ), ROS production ( 32 ), canonical intracellular signaling ( 249 ), central nervous system signaling via substrate supply ( 153 ) and protein lactylation ( 148 ), and gene expression via histone lactylation ( 30 , 250 ). With all due respect to classical and contemporary discoveries in metabolic regulation, it is reasonable to assert that “lactate is the major myokine and exerkine” because of its abundance, dynamic range of concentration change, effect on cell redox and multiple independent and coordinated regulatory effects on major metabolic pathways in diverse tissues ( 115 , 251 ). Lactate fuels the spiral mitochondrial reticulum at the base of the sperm head.…”

Section: Discussionmentioning

confidence: 99%

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Lactate as a myokine and exerkine: drivers and signals of physiology and metabolism

Brooks

Osmond

Arevalo

et al. 2023

Journal of Applied Physiology

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No longer viewed as a metabolic waste product and cause of muscle fatigue, a contemporary view incorporates the roles of lactate in metabolism, sensing and signaling in normal as well as pathophysiological conditions. Lactate exists in millimolar concentrations in muscle, blood and other tissues and can rise more than an order of magnitude as the result of increased production and clearance limitations. Lactate exerts its powerful driver-like influence by mass action, redox change, allosteric binding, and other mechanisms described in this article. Depending on the condition, such as during rest and exercise, following injury, or pathology, lactate can serve as a myokine or exerkine with autocrine-, paracrine-, and endocrine-like functions that have important basic and translational implications. For instance, lactate signaling is: involved in reproductive biology, fueling the heart, muscle and brain, controlling cardiac output and breathing, growth and development, and a treatment for inflammatory conditions. Ironically, lactate can be disruptive of normal processes such as insulin secretion when insertion of lactate transporters into pancreatic Beta-cell membranes is not suppressed and in carcinogenesis. Lactate signaling is important in areas of intermediary metabolism, redox biology, mitochondrial biogenesis, cardiovascular and pulmonary regulation, genomics, neurobiology, gut physiology, appetite regulation, nutrition and overall health and vigor. The various roles of lactate as a myokine and exerkine are reviewed.

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Section: Discussionmentioning

confidence: 99%

“…To summarize this section, it is fair to reiterate that the roles for lactate in regulation of gene and protein synthesis regulation are becoming recognized ( 115 ).…”

Section: The Forms Of Lactate Signalingmentioning

confidence: 99%

Lactate as a myokine and exerkine: drivers and signals of physiology and metabolism

Brooks

Osmond

Arevalo

et al. 2023

Journal of Applied Physiology

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“…Recently, we found post-exercise levels of N-lactoyl-phenylalanine (Lac-Phe), a pseudo-dipeptide shown to lower body weight in mice [10], to correlate with adipose tissue loss in subjects with obesity [11]. Other examples of exercise-regulated intermediary metabolites with extracellular signalling function include succinate, lactate, and beta-aminoisobutyric acid [8,[12][13][14]. In addition to endogenous metabolites, small molecules produced by the microbiota have been shown to modulate host energy metabolism and furthermore, immune cell function and inflammation [15,16].…”

Section: Introductionmentioning

confidence: 99%

Phenyllactic Acid is Physiologically Released from Skeletal Muscle and Contributes to the Beneficial Effects of Physical Exercise in Humans

Hoene,

Zhao,

et al. 2024

Preprint

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Methods We studied acute exercise- and training-induced changes in plasma metabolites in sedentary subjects with overweight (8 male, 14 female) participating in an eight-week supervised training program flanked by two acute endurance exercise sessions. Plasma metabolites were quantified using LC- and CE-MS. In a separate study (n=9 lean males), we assessed metabolite fluxes over the leg using arterial and venous catheters. Functional analyses were performed in primary blood mononuclear cells (PBMCs) stimulated with lipopolysaccharide (LPS) or the saturated fatty acid palmitate. Results The amino acid breakdown products 3-phenyllactic acid (PLA), 4-hydroxyphenyllactic acid and indolelactic acid were increased after both acute exercise and training. All three aromatic lactic acids, which so far mainly received attention as bacterial metabolites, exhibited an efflux from the leg. PLA showed the largest increase after both acute exercise and training, of 57% and 20% respectively. The magnitude of the acute exercise-induced increase in PLA correlated with a decrease in subcutaneous adipose tissue volume and an improvement in insulin sensitivity over the course of the intervention. Furthermore, both isomers, D and L-PLA, counteracted inflammatory cytokine production in PBMCs. Conclusions/interpretation Our findings indicate that PLA is physiologically released from skeletal muscle and can contribute to the anti-inflammatory effects of exercise as well as to individual difference in the response to lifestyle interventions in humans. PLA and potentially, aromatic lactic acids in general may be particularly relevant metabolic regulators because they can be produced both endogenously and by the microbiome.

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“…Lactate is a fundamental metabolite that has attracted significant biochemical and physiologic attention for over a century (1, 2). Classically, lactate is produced from glucose when energy demands are high, such as in muscle during exercise, and can reach millimolar concentrations in the circulation (3, 4). Once produced, lactate exerts pleotropic functions in systemic energy metabolism.…”

Section: Introductionmentioning

confidence: 99%

SLC17 transporters mediate renal excretion of Lac-Phe in mice and humans

Li,

Xiao,

Schlosser

et al. 2024

Preprint

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N-lactoyl-phenylalanine (Lac-Phe) is a lactate-derived metabolite that suppresses food intake and body weight. Little is known about the mechanisms that mediate Lac-Phe transport across cell membranes. Here we identify SLC17A1 and SLC17A3, two kidney-restricted plasma membrane-localized solute carriers, as physiologic urine Lac-Phe transporters. In cell culture, SLC17A1/3 exhibit high Lac-Phe efflux activity. In humans, levels of Lac-Phe in urine exhibit a strong genetic association with the SLC17A1-4 locus. Urine Lac-Phe levels are also increased following a Wingate sprint test. In mice, genetic ablation of either SLC17A1 or SLC17A3 reduces urine Lac-Phe levels. Despite these differences, both knockout strains have normal blood Lac-Phe and body weights, demonstrating that urine and plasma Lac-Phe pools are functionally and biochemically de-coupled. Together, these data establish SLC17 family members as the physiologic urine transporters for Lac-Phe and uncover a biochemical pathway for the renal excretion of this signaling metabolite.

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Lactate as a major myokine and exerkine

Cited by 22 publications

References 10 publications

Lactate as a myokine and exerkine: drivers and signals of physiology and metabolism

Lactate as a myokine and exerkine: drivers and signals of physiology and metabolism

Phenyllactic Acid is Physiologically Released from Skeletal Muscle and Contributes to the Beneficial Effects of Physical Exercise in Humans

SLC17 transporters mediate renal excretion of Lac-Phe in mice and humans

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