Oral application of L-menthol in the heat: From pleasure to performance

When menthol is applied to the oral cavity it presents with a familiar refreshing sensation and cooling mint flavour. This may be deemed hedonic in some individuals, but may cause irritation in others. This variation in response is likely dependent upon trigeminal sensitivity toward cold stimuli, suggesting a need for a menthol solution that can be easily personalised. Menthol’s characteristics can also be enhanced by matching colour to qualitative outcomes; a factor which can easily be manipulated by practitioners working in athletic or occupational settings to potentially enhance intervention efficacy. This presentation will outline the efficacy of oral menthol application for improving time trial performance to date, either via swilling or via co-ingestion with other cooling strategies, with an emphasis upon how menthol can be applied in ecologically valid scenarios. Situations in which performance is not expected to be enhanced will also be discussed. An updated model by which menthol may prove hedonic, satiate thirst and affect ventilation will also be presented, with the potential performance implications of these findings discussed and modelled. Qualitative reflections from athletes that have implemented menthol mouth swilling in competition, training and maximal exercise will also be included

The effectiveness of orally applied L-menthol on exercise performance in the heat

During exercise in the heat, increasing thermal load leads to thermo-behavioural adjustments in exercise performance, due to greater perceptual and physiological strain. Behavioural reductions in exercise intensity in the heat are initially mediated via rises in skin temperature, which alter thermal perception (comfort and sensation) and later by rises in core temperature, which increase cardiovascular strain and perceived exertion. Therefore, thermoregulation may be ordered and dependant on the magnitude, timing and/or prioritisation of afferent signals. Non-thermal cooling via L-menthol has been shown to enhance exercise performance in the early and latter stages when delivered orally at a concentration of 0.01%. Indeed, during periods of progressive thermal stress, imposed by the combination of maximal exercise and environmental heat and humidity, L-menthol has been shown to offer an immediate cooling stimulus thus extending exercise capacity. However, repeated administration of L-menthol during exercise in the heat, as thermal load increases, is unable to recover a decline in work rate. Therefore, it is unclear whether the potency of L-menthol is sustained upon frequent application and what strategies are needed in both sporting and occupational settings to optimise its effectiveness. In this part of the symposium we will consider oral delivery of L-menthol and its potential for reducing an individual’s perception of heat stress with associated effects on exercise tolerance in the heat. We will also examine the frequency of use, optimal concentration, timing and novelty of L-menthol in a sporting and occupational context

The application of menthol in sport, exercise and occupational settings: To apply, ingest or discard?

The cold-receptor agonist menthol has been utilised to improve performance by imparting feelings of coolness and freshness to alleviate thermal discomfort. These effects are mediated by peripheral cold-sensitive neurons and trigeminal nerves of the face and oral cavity via activation of TRPM8 channels by either applying, ingesting or swilling menthol solutions. The forcing function exerted by topically applied menthol is probably influenced by a combination of factors, including the percentage of body surface area (BSA) exposed, body region, and dose, but the weighting of each requires clarification, as do factors influencing oral administration. Topically, a greater menthol-mediated forcing function has been shown to alter thermoregulation resulting in heat gain, but the precise mechanisms require clarification. It is unknown whether there is a similar effect when menthol is administered orally, but higher concentrations are reportedly preferred. Consequently, menthol has the potential to improve thermal perception but evoke heat gain responses placing biophysical and behavioural thermoregulation in conflict. Nevertheless, there is a growing body of literature that supports the efficacy of menthol application to improve endurance performance and, more recently, muscular performance. Oral menthol application has been shown to improve time to exhaustion and time trial performance with emerging evidence in power based activities. Independently of the heat storage response, topically applied menthol has also been shown to improve endurance performance and enhance recovery from exercise-induced muscle damage, possibly due to increased motor unit activation. Both methods of application have consistently been shown to ameliorate subjective measures of thermal strain during exercise. Accordingly, the aim of this symposium is to present key literature on the perceptual, thermoregulatory and performance effects of menthol and actively debate the merits of: the medium of application, advised protocols for menthol use during these modalities, the timing of application and the resultant thermoregulatory effects

The influence of a menthol and ethanol soaked garment on human temperature regulation and perception during exercise and rest in warm, humid conditions

This study assessed whether donning a garment saturated with menthol and ethanol (M/E) can improve evaporative cooling and thermal perceptions versus water (W) or nothing (CON) during low intensity exercise and rest in warm, humid conditions often encountered in recreational/occupational settings. It was hypothesised there would be no difference in rectal (Tre) and skin (Tsk) temperature, infra-red thermal imagery of the chest/back, thermal comfort (TC) and rating of perceived exertion (RPE) between M/E, W and CON, but participants would feel cooler in M/E versus W or CON. Methods - Six volunteers (mean [SD] 22 [4] years, 72.4 [7.4] kg and 173.6 [3.7] cm) completed (separate days) three, 60-min tests in 30 °C, 70%rh, in a balanced order. After 15-min of seated rest participants donned a dry (CON) or 80 mL soaked (M/E, W) long sleeve shirt appropriate to their intervention. They then undertook 30-min of low intensity stepping at a rate of 12 steps/min on a 22.5 cm box, followed by 15-min of seated rest. Measurements included heart rate (HR), Tre, Tsk (chest/back/forearm), thermal imaging (back/chest), thermal sensation (TS), TC and RPE. Data were reported every fifth minute as they changed from baseline and the area under the curves were compared by condition using one-way repeated measures ANOVA, with an alpha level of 0.05. Results - Tre differed by condition, with the largest heat storage response observed in M/E (p<0.05). Skin temperature at the chest/back/forearm, and thermal imaging of the chest all differed by condition, with the greatest rate of heat loss observed in W and M/E respectively (p<0.01). Thermal sensation differed by condition, with the coolest sensations observed in M/E (p<0.001). No other differences were observed. Conclusions - Both M/E and W enhanced evaporative cooling compared CON, but M/E causes cooler sensations and a heat storage response, both of which are likely mediated by menthol

Mismatch Repair Genes Mlh1 and Mlh3 Modify CAG Instability in Huntington's Disease Mice: Genome-Wide and Candidate Approaches

The Huntington's disease gene (HTT) CAG repeat mutation undergoes somatic expansion that correlates with pathogenesis. Modifiers of somatic expansion may therefore provide routes for therapies targeting the underlying mutation, an approach that is likely applicable to other trinucleotide repeat diseases. Huntington's disease HdhQ111 mice exhibit higher levels of somatic HTT CAG expansion on a C57BL/6 genetic background (B6.HdhQ111) than on a 129 background (129.HdhQ111). Linkage mapping in (B6x129).HdhQ111 F2 intercross animals identified a single quantitative trait locus underlying the strain-specific difference in expansion in the striatum, implicating mismatch repair (MMR) gene Mlh1 as the most likely candidate modifier. Crossing B6.HdhQ111 mice onto an Mlh1 null background demonstrated that Mlh1 is essential for somatic CAG expansions and that it is an enhancer of nuclear huntingtin accumulation in striatal neurons. HdhQ111 somatic expansion was also abolished in mice deficient in the Mlh3 gene, implicating MutLγ (MLH1–MLH3) complex as a key driver of somatic expansion. Strikingly, Mlh1 and Mlh3 genes encoding MMR effector proteins were as critical to somatic expansion as Msh2 and Msh3 genes encoding DNA mismatch recognition complex MutSβ (MSH2–MSH3). The Mlh1 locus is highly polymorphic between B6 and 129 strains. While we were unable to detect any difference in base-base mismatch or short slipped-repeat repair activity between B6 and 129 MLH1 variants, repair efficiency was MLH1 dose-dependent. MLH1 mRNA and protein levels were significantly decreased in 129 mice compared to B6 mice, consistent with a dose-sensitive MLH1-dependent DNA repair mechanism underlying the somatic expansion difference between these strains. Together, these data identify Mlh1 and Mlh3 as novel critical genetic modifiers of HTT CAG instability, point to Mlh1 genetic variation as the likely source of the instability difference in B6 and 129 strains and suggest that MLH1 protein levels play an important role in driving of the efficiency of somatic expansions

Mismatch Repair Genes Mlh1 and Mlh3 Modify CAG Instability in Huntington\u27s Disease Mice: Genome-Wide and Candidate Approaches

The Huntington\u27s disease gene (HTT) CAG repeat mutation undergoes somatic expansion that correlates with pathogenesis. Modifiers of somatic expansion may therefore provide routes for therapies targeting the underlying mutation, an approach that is likely applicable to other trinucleotide repeat diseases. Huntington\u27s disease Hdh(Q111) mice exhibit higher levels of somatic HTT CAG expansion on a C57BL/6 genetic background (B6.Hdh(Q111) ) than on a 129 background (129.Hdh(Q111) ). Linkage mapping in (B6x129).Hdh(Q111) F2 intercross animals identified a single quantitative trait locus underlying the strain-specific difference in expansion in the striatum, implicating mismatch repair (MMR) gene Mlh1 as the most likely candidate modifier. Crossing B6.Hdh(Q111) mice onto an Mlh1 null background demonstrated that Mlh1 is essential for somatic CAG expansions and that it is an enhancer of nuclear huntingtin accumulation in striatal neurons. Hdh(Q111) somatic expansion was also abolished in mice deficient in the Mlh3 gene, implicating MutLγ (MLH1-MLH3) complex as a key driver of somatic expansion. Strikingly, Mlh1 and Mlh3 genes encoding MMR effector proteins were as critical to somatic expansion as Msh2 and Msh3 genes encoding DNA mismatch recognition complex MutSβ (MSH2-MSH3). The Mlh1 locus is highly polymorphic between B6 and 129 strains. While we were unable to detect any difference in base-base mismatch or short slipped-repeat repair activity between B6 and 129 MLH1 variants, repair efficiency was MLH1 dose-dependent. MLH1 mRNA and protein levels were significantly decreased in 129 mice compared to B6 mice, consistent with a dose-sensitive MLH1-dependent DNA repair mechanism underlying the somatic expansion difference between these strains. Together, these data identify Mlh1 and Mlh3 as novel critical genetic modifiers of HTT CAG instability, point to Mlh1 genetic variation as the likely source of the instability difference in B6 and 129 strains and suggest that MLH1 protein levels play an important role in driving of the efficiency of somatic expansions

High resolution time-course mapping of early transcriptomic, molecular and cellular phenotypes in Huntington\u27s disease CAG knock-in mice across multiple genetic backgrounds.

Huntington\u27s disease is a dominantly inherited neurodegenerative disease caused by the expansion of a CAG repeat in the HTT gene. In addition to the length of the CAG expansion, factors such as genetic background have been shown to contribute to the age at onset of neurological symptoms. A central challenge in understanding the disease progression that leads from the HD mutation to massive cell death in the striatum is the ability to characterize the subtle and early functional consequences of the CAG expansion longitudinally. We used dense time course sampling between 4 and 20 postnatal weeks to characterize early transcriptomic, molecular and cellular phenotypes in the striatum of six distinct knock-in mouse models of the HD mutation. We studied the effects of the HttQ111 allele on the C57BL/6J, CD-1, FVB/NCr1, and 129S2/SvPasCrl genetic backgrounds, and of two additional alleles, HttQ92 and HttQ50, on the C57BL/6J background. We describe the emergence of a transcriptomic signature in HttQ111/+  mice involving hundreds of differentially expressed genes and changes in diverse molecular pathways. We also show that this time course spanned the onset of mutant huntingtin nuclear localization phenotypes and somatic CAG-length instability in the striatum. Genetic background strongly influenced the magnitude and age at onset of these effects. This work provides a foundation for understanding the earliest transcriptional and molecular changes contributing to HD pathogenesis

Mercury's Weather-Beaten Surface: Understanding Mercury in the Context of Lunar and Asteroid Space Weathering Studies

Understanding the composition of Mercury's crust is key to comprehending the formation of the planet. The regolith, derived from the crustal bedrock, has been altered via a set of space weathering processes. These processes are the same set of mechanisms that work to form Mercury's exosphere, and are moderated by the local space environment and the presence of an intrinsic planetary magnetic field. The alterations need to be understood in order to determine the initial crustal compositions. The complex interrelationships between Mercury's exospheric processes, the space environment, and surface composition are examined and reviewed. The processes are examined in the context of our understanding of these same processes on the lunar and asteroid regoliths. Keywords: Mercury (planet) Space weathering Surface processes Exosphere Surface composition Space environment