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

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 carbohydrate nutrition, 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 adaptation, and brain executive function, growth and development, and a treatment for inflammatory conditions. Lactate also works with many other mechanisms and factors in controlling cardiac output and pulmonary ventilation during exercise. Ironically, lactate can be disruptive of normal processes such as insulin secretion when insertion of lactate transporters into pancreatic ß-cell membranes is not suppressed, and in carcinogenesis when factors that suppress carcinogenesis are inhibited, whereas factors that promote carcinogenesis are upregulated. Lactate signaling is important in areas of intermediary metabolism, redox biology, mitochondrial biogenesis, neurobiology, gut physiology, appetite regulation, nutrition, and overall health and vigor. The various roles of lactate as a myokine and exerkine are reviewed.NEW & NOTEWORTHY Lactate sensing and signaling is a relatively new and rapidly changing field. As a physiological signal lactate works both independently and in concert with other signals. Lactate operates via covalent binding and canonical signaling, redox change, and lactylation of DNA. Lactate can also serve as an element of feedback loops in cardiopulmonary regulation. From conception through aging lactate is not the only a myokine or exerkine, but it certainly deserves consideration as a physiological signal.

Epigenetic Responses to Acute Resistance Exercise in Trained vs. Sedentary Men.

Bagley, JR, Burghardt, KJ, McManus, R, Howlett, B, Costa, PB, Coburn, JW, Arevalo, JA, Malek, MH, and Galpin, AJ. Epigenetic responses to acute resistance exercise in trained vs. sedentary men. J Strength Cond Res 34(6): 1574-1580, 2020-Acute resistance exercise (RE) alters DNA methylation, an epigenetic process that influences gene expression and regulates skeletal muscle adaptation. This aspect of cellular remodeling is poorly understood, especially in resistance-trained (RT) individuals. The study purpose was to examine DNA methylation in response to acute RE in RT and sedentary (SED) young men, specifically targeting genes responsible for metabolic, inflammatory, and hypertrophic muscle adaptations. Vastus lateralis biopsies were performed before (baseline), 30 minutes after, and 4 hours after an acute RE bout (3 × 10 repetitions at 70% 1 repetition maximum [1RM] leg press and leg extension) in 11 RT (mean ± SEM: age = 26.1 ± 1.0 years; body mass = 84.3 ± 0.2 kg; leg press 1RM = 412.6 ± 25.9 kg) and 8 SED (age = 22.9 ± 1.1 years; body mass = 75.6 ± 0.3 kg; leg press 1RM = 164.8 ± 22.5 kg) men. DNA methylation was analyzed through methylation sensitive high-resolution melting using real-time polymerase chain reaction. Separate 2 (group) × 3 (time) repeated-measures analyses of variance and analyses of covariance were performed to examine changes in DNA methylation for each target gene. Results showed that acute RE (a) hypomethylated LINE-1 (measure of global methylation) in RT but not SED, (b) hypermethylated metabolic genes (GPAM and SREBF2) in RT, while lowering SREBF2 methylation in SED, and (c) did not affect methylation of genes associated with inflammation (IL-6 and TNF-α) or hypertrophy (mTOR and AKT1). However, basal IL-6 and TNF-α were lower in SED compared with RT. These findings indicate the same RE stimulus can illicit different epigenetic responses in RT vs. SED men and provides a molecular mechanism underpinning the need for differential training stimuli based on subject training backgrounds.

The Role of Peroxiredoxin 6 in Cell Signaling.

Peroxiredoxin 6 (Prdx6, 1-cys peroxiredoxin) is a unique member of the peroxiredoxin family that, in contrast to other mammalian peroxiredoxins, lacks a resolving cysteine and uses glutathione and π glutathione S-transferase to complete its catalytic cycle. Prdx6 is also the only peroxiredoxin capable of reducing phospholipid hydroperoxides through its glutathione peroxidase (Gpx) activity. In addition to its peroxidase activity, Prdx6 expresses acidic calcium-independent phospholipase A2 (aiPLA2) and lysophosphatidylcholine acyl transferase (LPCAT) activities in separate catalytic sites. Prdx6 plays crucial roles in lung phospholipid metabolism, lipid peroxidation repair, and inflammatory signaling. Here, we review how the distinct activities of Prdx6 are regulated during physiological and pathological conditions, in addition to the role of Prdx6 in cellular signaling and disease.

Muscle health and performance in monozygotic twins with 30 years of discordant exercise habits.

INTRODUCTION: Physical health and function depend upon both genetic inheritance and environmental factors (e.g., exercise training). PURPOSE: To enhance the understanding of heritability/adaptability, we explored the skeletal muscle health and physiological performance of monozygotic (MZ) twins with > 30 years of chronic endurance training vs. no specific/consistent exercise. METHODS: One pair of male MZ twins (age = 52 years; Trained Twin, TT; Untrained Twin, UT) underwent analyses of: (1) anthropometric characteristics and blood profiles, (2) markers of cardiovascular and pulmonary health, and (3) skeletal muscle size, strength, and power and molecular markers of muscle health. RESULTS: This case study represents the most comprehensive physiological comparison of MZ twins with this length and magnitude of differing exercise history. TT exhibited: (1) lower body mass, body fat%, resting heart rate, blood pressure, cholesterol, triglycerides, and plasma glucose, (2) greater relative cycling power, anaerobic endurance, and aerobic capacity (VO2max), but lower muscle size/strength and poorer muscle quality, (3) more MHC I (slow-twitch) and fewer MHC IIa (fast-twitch) fibers, (4) greater AMPK protein expression, and (5) greater PAX7, IGF1Ec, IGF1Ea, and FN14 mRNA expression than UT. CONCLUSIONS: Several measured differences are the largest reported between MZ twins (TT expressed 55% more MHC I fibers, 12.4 ml/kg/min greater VO2max, and 8.6% lower body fat% vs. UT). These data collectively (a) support utilizing chronic endurance training to improve body composition and cardiovascular health and (b) suggest the cardiovascular and skeletal muscle systems exhibit greater plasticity than previously thought, further highlighting the importance of studying MZ twins with large (long-term) differences in exposomes.

Fiber type-specific analysis of AMPK isoforms in human skeletal muscle: advancement in methods via capillary nanoimmunoassay.

Human skeletal muscle is a heterogeneous mixture of multiple fiber types (FT). Unfortunately, present methods for FT-specific study are constrained by limits of protein detection in single-fiber samples. These limitations beget compensatory resource-intensive procedures, ultimately dissuading investigators from pursuing FT-specific research. Additionally, previous studies neglected hybrid FT, confining their analyses to only pure FT. Here we present novel methods of protein detection across a wider spectrum of human skeletal muscle FT using fully automated capillary nanoimmunoassay (CNIA) technology. CNIA allowed a ~20-fold-lower limit of 5'-AMP-activated protein kinase (AMPK) detection compared with Western blotting. We then performed FT-specific assessment of AMPK expression as a proof of concept. Individual human muscle fibers were mechanically isolated, dissolved, and myosin heavy chain (MHC) fiber typed via SDS-PAGE. Single-fiber samples were combined in pairs and grouped into MHC I, MHC I/IIa, MHC IIa, and MHC IIa/IIx for expression analysis of AMPK isoforms α1, α2, ß1, ß2, γ2, and γ3 with a tubulin loading control. Significant FT-specific differences were found for α2 (1.7-fold higher in MHC IIa and MHC IIa/IIx vs. others), γ2 (2.5-fold higher in MHC IIa vs. others), and γ3 (2-fold higher in MHC IIa and 4-fold higher in MHC IIa/IIx vs. others). Development of a protocol that combines the efficient and sensitive CNIA technology with comprehensive SDS-PAGE fiber typing marks an important advancement in FT-specific research because it allows more precise study of the molecular mechanisms governing metabolism, adaptation, and regulation in human muscle. NEW & NOTEWORTHY We demonstrate the viability of applying capillary nanoimmunoassay technology to the study of fiber type-specific protein analysis in human muscle fibers. This novel technique enables a ~20-fold-lower limit of protein detection compared with traditional Western blotting methods. Combined with SDS-PAGE methods of fiber typing, we apply this technique to compare 5'-AMP-activated protein kinase isoform expression in myosin heavy chain (MHC) I, MHC I/IIa, MHC IIa, and MHC IIa/IIx fiber types.

Lower-Limb Dominance, Performance, and Fiber Type in Resistance-trained Men.

INTRODUCTION: Large imbalances between limbs are common and potentially dangerous, yet few studies have simultaneously examined performance and physiological asymmetries. The current study examined the associations between lower-limb dominance, drop-jumping kinematics, maximal strength, and myosin heavy-chain (MHC) fiber type in the vastus lateralis. METHODS: Thirteen resistance-trained men (age, 24.3 ± 2.7 yr; height, 181.4 ± 6.6 cm; mass, 87.7 ± 11.3 kg) identified their dominant (DOM) and nondominant (ND) limb, performed drop jumps (30 cm) and maximal knee extensions (1-repetition maximum, or 1RM), and provided biopsies from both vastus lateralis muscles for single-fiber (109 ± 36 per limb per person) MHC fiber-type identification (FT%). RESULTS: All participants selected "right" as the "preferred kicking limb" (DOM). DOM displayed a trend for a greater eccentric knee angular velocity (EKV; P = 0.083) and a significantly greater concentric knee angular velocity (CKVl P = 0.002) during drop jump. DOM also tended to be stronger than ND (64.3 ± 11.3 vs 61.0 ± 8.8 kg, P = 0.063). Slow-twitch (MHC I) fibers were more prevalent in DOM (P < 0.025), whereas ND contained more fast-twitch (MHC IIa; P < 0.025). No correlations existed between categories (jumping, 1RM, and FT%). Asymmetries of >5% were present in 6 of 12 participants for EKV, 2 of 12 for CKV, 6 of 13 for 1RM, 12 of 13 for MHC I, and 11 of 13 for MHC IIa. However, only a single participant expressed asymmetries of >5% in all dependent variables (EKV, CKV, 1RM, MHC I, and MHC IIa). CONCLUSIONS: Several statistically and clinically relevant asymmetries were identified. The FT% differences between lower limbs were large and common. The findings also seem to conclude that DOM was stronger, moved faster, and contained more MHC I. However, only 23% of participants actually displayed that result. This highlights the need to analyze and report both group and individual data, particularly when interpreting findings across multiple related, but not necessarily causal, measurements.

Improving human skeletal muscle myosin heavy chain fiber typing efficiency.

Single muscle fiber sodium dodecyl sulfate polyacrylamide gel-electrophoresis (SDS-PAGE) is a sensitive technique for determining skeletal muscle myosin heavy chain (MHC) composition of human biopsy samples. However, the number of fibers suitable to represent fiber type distribution via this method is undefined. Muscle biopsies were obtained from the vastus lateralis (VL) of nine resistance-trained males (25 ± 1 year, height = 179 ± 5 cm, mass = 82 ± 8 kg). Single fiber MHC composition was determined via SDS-PAGE. VL fiber type distribution [percent MHC I, I/IIa, IIa, IIa/IIx, and total "hybrids" (i.e. I/IIa + IIa/IIx)] was evaluated according to number of fibers analyzed per person (25 vs. 125). VL fiber type distribution did not differ according to number of fibers analyzed (P > 0.05). VL biopsy fiber type distribution of nine subjects is represented by analyzing 25 fibers per person. These data may help minimize cost, personnel-time, and materials associated with this technique, thereby improving fiber typing efficiency in humans.