Skeletal Muscle Lactate Metabolism Research Articles

MicroRNA-92b in the skeletal muscle regulates exercise capacity via modulation of glucose metabolism.

Exercise mimetics is a proposed class of therapeutics that specifically mimics or enhances the therapeutic effects of exercise. Muscle glycogen and lactate extrusion are critical for physical performance. The mechanism by which glycogen and lactate metabolism are manipulated during exercise remains unclear. This study aimed to assess the effect of miR-92b on the upregulation of exercise training-induced physical performance. Adeno-associated virus (AAV)-mediated skeletal muscle miR-92b overexpression in C57BLKS/J mice, and global knockout of miR-92b mice were used to explore the function of miR-92b in glycogen and lactate metabolism in skeletal muscle. AAV-mediated UGP2 or MCT4 knockdown in WT or miR-92 knockout mice was used to confirm whether miR-92b regulates glycogen and lactate metabolism in skeletal muscle through UGP2 and MCT4. Body weight, muscle weight, grip strength, running time and distance to exhaustion, and muscle histology were assessed. The expression levels of muscle mass-related and function-related proteins were analysed by immunoblotting or immunostaining. Global knockout of miR-92b resulted in normal body weight and insulin sensitivity, but higher glycogen content before exercise exhaustion (0.8538±0.0417 vs. 1.043±0.040, **P=0.0087), lower lactate levels after exercise exhaustion (4.133±0.2589 vs. 3.207±0.2511, *P=0.0279), and better exercise capacity (running distance to exhaustion, 3616±86.71 vs. 4231±90.29, ***P=0.0006; running time to exhaustion, 186.8±8.027 vs. 220.8±3.156, **P=0.0028), as compared with those observed in the control mice. Mice skeletal muscle overexpressing miR-92b (both miR-92b-3p and miR-92b-5p) displayed lower glycogen content before exercise exhaustion (0.6318±0.0231 vs. 0.535±0.0194, **P=0.0094), and higher lactate accumulation after exercise exhaustion (4.5±0.2394 vs. 5.467±0.1892, *P=0.01), and poorer exercise capacity (running distance to exhaustion, 4005±81.65 vs. 3228±149.8, ***P<0.0001; running time to exhaustion, 225.5±7.689 vs. 163±6.476, **P=0.001). Mechanistic analysis revealed that miR-92b-3p targets UDP-glucose pyrophosphorylase 2 (UGP2) expression to inhibit glycogen synthesis, while miR-92b-5p represses lactate extrusion by directly target monocarboxylate transporter 4 (MCT4). Knockdown of UGP2 and MCT4 reversed the effects observed in the absence of miR-92b in vivo. This study revealed regulatory pathways, including miR-92b-3p/UGP2/glycogen synthesis and miR-92b-5p/MCT4/lactate extrusion, which could be targeted to control exercise capacity.

A method for calculating lactate production rate using blood lactate concentration during exercise in mice

Introduction Lactate acts as an energy fuel (Brooks, 2018) and a signaling molecule for muscle metabolic adaptation such as mitochondrial biogenesis (Hashimoto et al., 2007). Lactate production rate is an important parameter for muscle metabolic adaptation but the measurement requires muscle biopsy in general. Blood lactate concentration is lower invasive and widely measured in sports. It is meaningful to establish a method to calculate lactate production rate from blood lactate concentration. The purpose of this study was to establish a method to determine the amount of lactate production from blood lactate concentration in mice. Methods C57BL6/L mice divided into two groups: a control group (CON) and an endurance treadmill training (EX) for 6 weeks (15~25 m/min; 30 min/day; 5 days/week). A lactate tolerance test was performed following i.p. injection of sodium lactate (1 g/kg of body weight). Blood lactate concentration was measured for 120 min after lactate injection, and lactate uptake capacity “k” was calculated from the following equation d[lactate]/dt = k[lactate]n Next, animals were subjected to an incremental exercise test (increasing from 10 m/min to 40 m/min) of 2 min run and 2 min rest on the treadmill, and blood lactate concentration was measured at each intensity. Lactate production at each intensity was calculated by combining the blood lactate concentration with the calculated lactate uptake capacity. We measured monocarboxylate transporter (MCT) 1 and 4 protein levels and citrate synthase (CS) activity. These are involved in lactate metabolism in skeletal muscle. To verify calculated lactate production, we measured muscle glycogen concentration after 10 bouts of 2 min run at each speed (0, 10, 20, 30 and 40 m/min) with 2 min rest using other control mice. Results We calculated “k” using time series data of lactate concentration after lactate injection. When the lactate concentration dynamics were computationally simulated with various “k”, it was found that lactate reduction rate was determined by k. However, “k” was not altered by 6 wk-endurance training. In the incremental exercise test, the blood lactate concentration in the EX group was significantly lower at 25-40 m/min than in the CON group (p<0.05). The lactate production rate in the EX group was also significantly lower at 35 and 40 m/min than in the CON group (p<0.05). These results suggest that lower lactate concentration during higher intensity exercise is attributable by lower lactate production rate in the EX group. Endurance training also decreased MCT4 protein (p<0.05), which acts release of lactate from muscle, and increased CS activity (p<0.05). These results support the lower lactate production rate in the EX group. Finally, we assessed whether the lactate production rate was valid by the measurement of muscle glycogen concentration after acute exercise at each exercise intensity. We confirmed there was a strong negative correlation between the muscle glycogen concentrations immediately after exercises and the calculated lactate production rates (r=0.99, p<0.01). [Conclusion] We established a reasonable method for calculating lactate production rate from blood lactate concentration during exercise.

Progression of Cancer Cachexia Alters Muscle Lactate Metabolism In ApcMin/+ Mice

Roughly 100,000 individuals are diagnosed with colorectal cancer a year, 80% of these cases arise from adenomatous polyps. A mutation of the tumor suppressor gene, Adenomatous polyposis coli (Apc) results in multiple intestinal neoplasia (Min), thus the Apc (Min/+) mouse is a common colorectal cancer model. Cancer cells favor a highly glycolytic environment. As such, there is an induction of processes regulating lactate metabolism and lactate shuttling. How colorectal cancer influences skeletal muscle lactate metabolism is uncertain. Purpose: We investigated how muscle lactate metabolism is regulated during the progression of cancer cachexia in Apc (Min/+) mice. Methods: Male Min/+mice (n = 17) were classified by body mass loss: weight stable (WS, 蠄 5%, n = 5), and cachectic (CC, 6‐19%; n = 5). C57BL/6J (B6, n = 6) served as controls. Quadriceps muscle samples were extracted and real‐time PCR was conducted to quantify lactate‐related gene expression. Results: LDH‐A was reduced 47% in the CC mice compared to the WS mice (p &lt; 0.05), while LDH‐B was not changed with cancer cachexia progression (p = 0.09). Monocarboxylate transporter 1 (MCT1) was induced 1.9‐fold in CC mice (p &lt; 0.05) compared to the B6 mice. MCT4 was induced 1.7‐fold and 2.3‐fold in the CC mice compared to B6 and WS mice, respectively. Muscle CD147 was not changed with cancer cachexia progression (p = 0.31).ConclusionThe progression of cachexia in mice with colon cancer alters markers of lactate metabolism that may play a role in muscle wasting associated with cachexia.

Lactate kinetics in human tissues at rest and during exercise

Lactate production in skeletal muscle has now been studied for nearly two centuries and still its production and functional role at rest and during exercise is much debated. In the early days skeletal muscle was mainly seen as the site of lactate production during contraction and lactate production associated with a lack of muscle oxygenation and fatigue. Later it was recognized that skeletal muscle not only played an important role in lactate production but also in lactate clearance and this led to a renewed interest, not the least from the Copenhagen School in the 1930s, in the metabolic role of lactate in skeletal muscle. With the introduction of lactate isotopes muscle lactate kinetics and oxidation could be studied and a simultaneous lactate uptake and release was observed, not only in muscle but also in other tissues. Therefore, this review will discuss in vivo human: (1) skeletal muscle lactate metabolism at rest and during exercise and suggestions are put forward to explain the simultaneous lactate uptake and release; and (2) lactate metabolism in the heart, liver, kidneys, brain, adipose tissue and lungs will be discussed and its potential importance in these tissues.

Study of Energy Metabolism of Skeletal Muscles in Alcoholic Liver Disease—Expired Gas Analysis During Exercise

The effects of chronic alcohol intake on skeletal muscle are clinically observed as muscle cramps with decrease in the amount of muscle. It was clarified by expired gas analysis that acute alcohol load affects disturbed energy metabolism of skeletal muscle. We studied abnormal energy metabolism of skeletal muscles in alcoholic liver diseases using expired gas analysis. Subjects of the study were five inpatients with alcoholic liver disease (fatty liver: one case, hepatic fibrosis: one case, liver cirrhosis: three case). Expired gas analysis during exercise was performed using AEROMONITOR. Minute ventilation, oxygen consumption and carbon dioxide output were monitored, and anaerobic threshold (AT) and respiratory compensation point (RCP) were calculated. The anaerobic threshold, which is the limit of the aerobic exercise, was significantly reduced in patients with alcoholic disease (p < 0.01). The respiratory compensation point, which is the limit of the metabolic compensation of intracellular lactic acidosis, was decreased (p < 0.01). The results of expired gas analysis during exercise indicate that the aerobic energy metabolism of skeletal muscle had been disturbed in alcoholic liver disease. The reduced RCP suggests that the lactate metabolism in skeletal muscle is also disturbed in alcoholic liver disease. Expired gas analysis during exercise allows determination of the amount of exercise required to treat liver diseases through analysis of AT.

Lactate as a fuel for mitochondrial respiration

Lactate production in skeletal muscle has now been studied for nearly two centuries and still its production and functional role at rest and during muscle contraction is a subject of debate. Historically, skeletal muscle was seen mainly as the site of lactate production during contraction and lactate production associated with a lack of muscle oxygenation and fatigue. Later, it was recognized that skeletal muscle not only plays an important role in lactate production but also in lactate clearance and this in turn has led to a renewed interest in the metabolic fate of lactate in skeletal muscle and also in other tissues. Studies using lactate isotopes have shown that skeletal muscle extracts lactate from the circulation despite a substantial net lactate release, and that skeletal muscle has a large capacity for lactate oxidation; these processes being enhanced with exercise. Lactate dehydrogenase (LDH) controls the formation of lactate and may regulate the turnover of lactate in the muscle cell. Skeletal muscle contains five LDH isoforms (LDH1-5). Of the five LDH isoforms, the heart-specific LDH1, 2 is generally suggested to favour the reaction of lactate to pyruvate whereas the muscle-specific LDH4,5 isoform favours lactate formation. However, in this paper, it is argued that compartmentalization of the muscle cell and LDH association with cell structures may play a more predominant role in whether the LDH reaction proceeds towards lactate or pyruvate formation. The model for skeletal muscle lactate metabolism presented is in essence based on a synthesis of old and more recent studies on skeletal muscle lactate transport, uptake, release, oxidation, and the role of LDH at rest and during exercise.

Chronic infusion of interleukin 1 induces hyperlactatemia and altered regulation of lactate metabolism in skeletal muscle.

Hyperlactatemia is observed commonly in patients with severe inflammation syndrome or sepsis. Elevated plasma lactate concentrations may be caused by cytokine-mediated alterations in specific organ systems responsible for lactate homeostasis. The role of interleukin 1 (IL-1) in inducing hyperlactatemia and derangements in skeletal muscle and hepatic lactate metabolism was investigated by examining the consequences of infusing IL-1 continuously into normal rats. Male Sprague-Dawley rats were anesthetized, and catheters were placed in the jugular vein. Rats were allowed to recover for 48 hours and were infused subsequently with either saline (control) or human recombinant IL-1alpha (20 microg/kg/d) for 6 days. On day 6, plasma, liver, and muscle samples were extracted and assayed for lactate and pyruvate dehydrogenase (PDH) activity. Plasma glucose concentrations were not different in the two groups. IL-1 infusion resulted in a twofold (p < .05) increase in the plasma lactate concentration compared with controls. IL-1 infusion also resulted in an elevated lactate content in skeletal muscle (p < .05) but not in liver. The proportion of PDH in the active form (PDHa) was reduced significantly (p < .05) in the skeletal muscle of animals infused with IL-1 compared with controls. In contrast to muscle, hepatic PDHa did not differ between the two groups. Total PDH complex activity was not affected in either liver or skeletal muscle. IL-1 infusion results in hyperlactatemia, increased skeletal muscle lactate, and a reduced PDHa in skeletal muscle. We conclude that IL-1 is a potential mediator of the derangements in lactate metabolism in skeletal muscle but not in liver.

Lactate turnover at rest and during submaximal exercise in patients with heart failure

Systemic and lower limb skeletal muscle lactate metabolism was studied in 10 men with congestive heart failure by use of a primed continuous intravenous infusion of L-(+)-[U-14C]lactate. Arterial and deep femoral venous blood samples were obtained at rest and during 30 min of submaximal exercise. Systemic lactate metabolic turnover rate (Rd) was determined using Steele's isotopic steady-state equation (Rd = isotopic infusion rate/arterial specific activity). Plasma lactate concentrations in the artery and deep femoral vein did not change significantly from resting values during exercise (1.11 +/- 0.13 vs. 1.26 +/- 0.12 and 1.27 +/- 0.12 vs. 1.30 +/- 0.12 mM, respectively), whereas Rd increased from 22.5 +/- 1.8 to 41.6 +/- 4.8 mumol.kg-1.min-1 (P < 0.005). Rd did not significantly correlate with arterial lactate concentration during rest or exercise. Because of simultaneous uptake and release of lactate in skeletal muscle, arterial and deep femoral venous lactate concentrations are not closely related to either systemic or lower limb skeletal muscle lactate metabolism in patients with congestive heart failure.

Plasma catecholamine and corticosterone and their in vitro effects on lizard skeletal muscle lactate metabolism

Lizard skeletal muscles utilize primarily lactate as a gluconeogenic substrate for glycogen replenishment following exercise. To understand the influence of selected hormones on this process, we measured changes in plasma catecholamines and corticosterone resulting from exercise in the lizard Dipsosaurus dorsalis and then investigated the physiological effects of those hormones on skeletal muscle lactate and glucose metabolism in vitro. Plasma epinephrine (Epi), norepinephrine, and corticosterone (Cort) increased 5.8, 10.2, and 2.2 times, respectively, after 5 min of exhaustive exercise. Epi and Cort levels remained elevated after 2 h of recovery. Skeletal muscle fiber bundles isolated from the red and white regions of the iliofibularis muscle were incubated 2 h at 40 degrees C in the presence of postexercise concentrations of [14C]lactate (15 mM) and glucose (8.5 mM) in the presence and absence of Epi or Cort. Red muscle oxidized both substrates at 2-3 times the rate of white muscle, and both red and white fibers oxidized lactate at 5-10 times the rate of glucose oxidation. Epi had a stimulatory effect on lactate oxidation by white muscle. Lactate incorporation into glycogen proceeded at 2-3 times the rate of glucose incorporation in both muscle types, with rates in red muscle again 2-3 times that for white muscle. Epi stimulated lactate carbon incorporation into glycogen by 50-140% in both red and white muscle but had no effect on glucose incorporation into glycogen in either tissue. We interpret these data as evidence that epinephrine stimulates lactate removal by skeletal muscle. Cort had no effect on lactate metabolism in either muscle type.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood lactate levels do not closely reflect skeletal muscle lactate metabolism in congestive heart failure

Blood lactate levels do not closely reflect skeletal muscle lactate metabolism in congestive heart failure