Skeletal muscle adaptations to heat therapy

Abstract

The therapeutic effects of heat have been harnessed for centuries to treat skeletal muscle disorders and other pathologies. However, the fundamental mechanisms underlying the well-documented clinical benefits associated with heat therapy (HT) remain poorly defined. Foundational studies in cultured skeletal muscle and endothelial cells, as well as in rodents, revealed that episodic exposure to heat stress activates a number of intracellular signaling networks and promotes skeletal muscle remodeling. Renewed interest in the physiology of HT in recent years has provided greater understanding of the signals and molecular players involved in the skeletal muscle adaptations to episodic exposures to HT. It is increasingly clear that heat stress promotes signaling mechanisms involved in angiogenesis, muscle hypertrophy, mitochondrial biogenesis, and glucose metabolism through not only elevations in tissue temperature but also other perturbations, including increased intramyocellular calcium and enhanced energy turnover. The few available translational studies seem to indicate that the earlier observations in rodents also apply to human skeletal muscle. Indeed, recent findings revealed that both local and whole-body HT may promote capillary growth, enhance mitochondrial content and function, improve insulin sensitivity and attenuate disuse-induced muscle wasting. This accumulating body of work implies that HT may be a practical treatment to combat skeletal abnormalities in individuals with chronic disease who are unwilling or cannot participate in traditional exercise-training regimens.

INTRODUCTION

Regular exposure to heat therapy (HT) in the form of sauna and hot baths has been used for medicinal purposes, including the treatment of skeletal muscle disorders, since ancient times (1, 3). These practices continue to be integral to several cultures, and large-scale studies strongly attest to the health-enhancing properties of chronic whole body heat stress (36). Numerous devices and technologies have also been developed to harness the therapeutic effects of topical heat. Among other modalities, heat pads and wraps, tube-lined garments, warm whirlpool baths and short-wave diathermy are widely used in the rehabilitation of skeletal muscle injuries and in the management of conditions associated with chronic pain and increased stiffness (41). Despite proven clinical benefits, the fundamental cellular and molecular mechanisms underpinning the therapeutic effects of HT remained, until recently, largely unexplored. Renewed interest in the topic and, particularly, the utilization of molecular biology techniques, catalyzed the discovery that heat stress has a profound impact on a number of signaling pathways, including angiogenesis (2, 20, 21, 35, 51), anabolism (13, 15, 32, 59), mitochondrial biogenesis (17, 18, 38, 58), and glucose homeostasis (8, 11, 16, 22, 34). Indeed, accumulating evidence indicates that repeated episodic exposures to HT may promote capillary growth and hypertrophy, increase mitochondrial content and function, and alter glucose metabolism and insulin signaling (Fig. 1).

Fig. 1.

Overview of the experimental evidence on the impact of heat stress on skeletal muscle angiogenesis, regulation of muscle mass, mitochondrial biogenesis and function, and glucose metabolism and insulin signaling. A wide range of models have been used to assess the molecular mechanisms and functional adaptations to single or multiple bouts of heat stress, including 1) temporary incubation of skeletal muscle (mouse and rat myoblasts) (15, 38, 44, 45) and endothelial cells (bovine aortic, human umbilical vein, and human dermal microvascular cells) (20, 28, 51) at temperatures ranging from ~39–42°C; 2) incubation of isolated muscles (rat epitrochlearis, extensor digitorum longus, and soleus) (11, 16, 34) and arteries (human skeletal muscle feed arteries from the axillary and inguinal regions) (28) at temperatures ranging from 38 to 42°C; 3) exposure of mice (2, 8, 33, 58), rats (6, 16, 42, 59), and hamsters (25) to episodic increases in core body temperature elicited by immersion in warm water, heated chambers, and electric heating pads; and 4) treating humans with local (14, 17, 18, 30, 31, 35) and whole body (10, 21, 22) heat therapy modalities. HS, heat stress; eNOS, endothelial nitric oxide synthase; mTOR, mammalian target of rapamycin.

The study of skeletal muscle adaptations to HT has its historical foundations in the discovery that heat shock produces the rapid upregulation of the so-called heat shock proteins (HSPs) and, consequently, augments the cellular tolerance to a number of stressors, including hypoxia, ischemia, and inflammation (61). Recognizing the critical importance of this large and highly conserved family of stress management proteins for a number of cellular processes, the early studies on the acute and long-term effects of HT on skeletal muscle used heat stress as a nonpharmacological experimental strategy to induce and harness the protective effects of HSPs (2, 6, 15, 25, 42). These and subsequent studies revealed that heat stress upregulates the expression in skeletal muscle of several members of the HSP family (15, 32, 48–50, 53, 59). Although this response is well documented, it remains unclear whether the activation of HSPs is imperative for the skeletal muscle adaptations to repeated HT.

This mini-review will present a summary of some of the major recent breakthroughs that have helped unravel the mechanistic basis underlying the skeletal muscle adaptations to both local and whole body HT. The main theme is that increased tissue temperature upon exposure to HT provokes a host of hemodynamic and metabolic adjustments and activates key signaling pathways involved in skeletal muscle remodeling. These initial stimuli generate secondary signals (e.g., increased vascular wall shear stress, calcium influx, and enhanced ATP turnover) that promote other signaling mechanisms and amplify the primary response. If episodically repeated, HT may ultimately lead to alterations in skeletal muscle structure and function. We focus on the signals and putative molecular players involved in four central adaptations to HT: 1) capillary growth, 2) muscle hypertrophy, 3) mitochondrial biogenesis, and 4) improved insulin and glucose signaling (Fig. 1). The reader is referred to other reviews describing the evidence for HT to promote recovery from muscle damage, attenuate atrophy during muscle disuse, and to accelerate recovery following exercise (39, 43).

ANGIOGENESIS

The seminal experiments of Ikeda et al. (25) first revealed that heat stress in the form of dry sauna enhances the content of the enzyme endothelial nitric oxide synthase (eNOS), a key regulator of vasomotor function and vascular remodeling. Motivated by earlier reports that sauna therapy enhances cardiac output and blood flow, these authors hypothesized that episodic increases in vascular wall shear stress during exposure to repeated sauna therapy would upregulate arterial eNOS expression in hamsters (25). Confirming this prediction, brief daily exposure to an experimental dry sauna system for 4 wk resulted in increased eNOS content in the endothelial cells of the aorta, carotid, femoral, and coronary arteries (25). The vital influence eNOS exerts on the functional and structural vascular adaptations to repeated heat stress was demonstrated by the same group of investigators in experiments in a mouse model of peripheral vascular insufficiency produced by excision of the femoral artery and vein. Akasaki et al. (2) showed that dry sauna at 41°C for 15 min and then at 34°C for 20 min once daily for 5 wk increased eNOS expression, accelerated blood flow recovery, and augmented ischemia-induced angiogenesis in skeletal muscle of apolipoprotein E-deficient mice. Most importantly, the changes in blood flow and capillary growth were absent in mice treated with the NOS inhibitor N^G-nitro-l-arginine methyl ester, as well as in eNOS-knockout mice, implicating nitric oxide (NO) as a central mediator of heat-induced angiogenesis in ischemic muscle (2). These groundbreaking findings that repeated whole body HT promotes capillary growth were later confirmed in additional studies in models of hindlimb ischemia (24, 40) and myocardial infarction (55).

The extensive work in preclinical models paved the way for studies aimed at examining the impact of heat stress on angiogenesis in human skeletal muscle. Kuhlenholter et al. (35) first investigated the effect of a single 90-min session of HT on the mRNA expression of proangiogenic factors in the vastus lateralis muscle of healthy young individuals. A tube-lined garment perfused with warm water was used to induce both local (single thigh) and lower-body heat stress. This study revealed that in addition to members of the HSP family, HT augmented the expression of several proangiogenic factors, including vascular endothelial growth factor and angiopoetin-1 (35). Of note, however, the mRNA expression of eNOS was not significantly altered by either topical or lower-body HT, which indicates that repeated rather than a single exposure to HT may be necessary to upregulate eNOS expression. In agreement with the studies in rodents (2, 20, 25), it was recently demonstrated that periodic exposure to HT for 6–8 wk enhances eNOS content in biopsies from the vastus lateralis muscle in humans (21, 31).

The confirmation that repeated HT elicits capillary growth in human skeletal muscle was made recently by Hesketh et al. (21). These authors exposed young sedentary male subjects to whole body HT in the form of a heat chamber at 40°C and ~40% humidity three times/wk for 6 wk. Capillary density and the capillary-fiber perimeter exchange index in the vastus lateralis increased by 21% and 15%, respectively, after the treatment, in conjunction with elevated endothelial-specific eNOS content (21). These changes were comparable to those elicited by time-matched, moderate-intensity exercise training, thus suggesting that whole body HT may be a practical treatment to combat skeletal muscle capillary rarefaction in individuals with chronic disease conditions who cannot participate or fail to adhere to traditional exercise training (21). Similar to whole body HT, local thigh heating using a tube-lined garment has been shown to affect skeletal muscle capillarization (31). Kim et al. (31) showed that 8 wk of local HT averted a temporal decline in the number of capillaries around type 2, but not type 1, fibers in the vastus lateralis muscle of young individuals.

The use of cultured endothelial cells and isolated vessels exposed to heat stress helped unveil the concept that elevated temperature is a primary stimulus underlying the effect of HT on angiogenesis. These experimental methods permit the examination of the impact of temperature on angiogenic signaling in the absence of confounding mechanisms that likely contribute to HT-induced angiogenesis, such as increased blood flow. Harris et al. (20) were among the first to report that exposure of cultured endothelial cells to heat stress (42°C for 1 h) increases eNOS expression and maximal bradykinin-stimulated NO release. Similarly, human skeletal muscle feed arteries exposed to 39°C for 60 min displayed increased eNOS protein expression (28). Rattan et al. (51) investigated the effect of exposing both human umbilical vein endothelial cells and human dermal microvascular endothelial cells to heat stress on angiogenesis in vitro, as assessed using a standardized tube formation assay. Preexposure to heat treatment at 41°C for 1 h enhanced capillary-like tube formation, which is indicative of enhanced angiogenic activity (51). These findings were strengthened by the report by Li et al. (37) of enhanced formation of microvessel-like structures in cocultures of primary human osteoblasts and outgrowth endothelial cells exposed to 41°C twice per week over 7–14 days.

The activation of temperature-sensitive mechanisms during HT treatment leads to increased blood flow and, consequently, enhanced shear stress, a potent inducer of angiogenesis in skeletal muscle (4). Chiesa et al. (7) showed that both single-leg and intense whole body heat stress led to progressive increases in blood flow and shear rates in the three major arteries of the leg alongside the virtual abolition of oscillatory shear profiles within these vessels. These findings illustrate the notion that elevated shear stress may act as a secondary signal to further stimulate angiogenesis during exposure to HT. A third, previously unrecognized mechanism that may contribute to HT-induced angiogenesis is the release in the circulation of factors that activate endothelial cell proliferation and migration (5). Brunt et al. (5) reported that exposing cultured endothelial cells to serum collected from individuals who had undergone whole body HT for 8 wk increased endothelial tubule formation and eNOS abundance. Although the exact identity of the factor(s) that mediate this effect is unknown, these findings suggest that systemic cardiovascular and metabolic adjustments that occur during whole body HT, and perhaps to a lesser extent during local HT, may trigger the production of substances capable of exerting an effect on endothelial cells (5).

REGULATION OF MUSCLE MASS

The pioneering work of Naito et al. (42) revealed that exposure to whole body heat stress attenuates disuse-induced muscle atrophy in rats. The premise behind this experiment was that heat-induced upregulation of HSPs, most notability heat shock protein 70 (Hsp70), would confer protection against the reduction in protein synthesis during non-weight-bearing activity (42). To test this hypothesis, adult female Sprague-Dawley rats were placed in an environmentally controlled heat chamber (41°C) for 60 min before undergoing hindlimb unweighting for 8 days. The hindlimb unweighting-induced loss of soleus muscle weight was 32% less in the animals exposed to a single session of HT compared with the control group. This was accompanied by a marked increase in the expression of Hsp70. Although this experiment did not establish a causal relationship between the upregulation of Hsp70 and the attenuation of muscle atrophy, it served as the foundation for a number of subsequent studies that confirmed that HT is not only an effective countermeasure against disuse-induced reduction in protein synthesis (46, 53, 57), but also a potent therapy to induce hypertrophy in healthy skeletal muscle (32, 47, 49, 59).

In a series of experiments in cultured cells, rodents, and subsequently in humans, Goto and colleagues (12–15, 59) established the concept that mild heat stress elicits skeletal muscle hypertrophy and provided unique insights into the cellular mechanisms underlying this phenomena. On the basis of the earlier report that chicks exposed to mild environmental heat stress (37.5 ± 0.1°C) for 24 h during their first week of life had higher body and breast muscle weights at later ages (19), these authors first examined the impact of a brief increase in the temperature of cultured rat skeletal muscle cells (L6) on cellular protein concentrations (15). These initial experiments revealed that incubation of L6 for 1 h at 41°C led to a 20% increase in protein concentration relative to the untreated cells and prompted the hypothesis that a single episodic exposure to HT would result in increased muscle mass in vivo (15). Indeed, a follow up study revealed that the soleus muscle wet weight relative to body weight of rats exposed to a single HT session in a heat chamber (41°C for 60 min) was significantly higher relative to the muscles harvested from control animals 7 days after the treatment (59). This response was later shown to be dependent on temperature, time, and frequency of exposure to the treatment (13).

To verify whether the beneficial effects of HT observed in rodents would also occur in human skeletal muscle, Goto et al. (14) examined the effects of repeated prolonged local heating using a heat- and steam-generating sheet on thigh muscle size and function. Eight men had one randomly selected thigh exposed to local HT for 8 h/day, 4 days/wk over 10 wk. On average, the heat- and steam-generating sheet placed on the thigh caused the temperature of the vastus lateralis muscle to increase by ~3°C. These experiments revealed that repeated topical HT increased maximal isometric torque, as well as the cross-sectional area of the knee extensors (14). The ergogenic effects of local HT were further documented in the recent studies of Kim et al. (31). Local heating using a tube-lined garment perfused with water at ~52°C daily for 8 consecutive weeks (90 min/day, 5 days/wk) enhanced the strength of the knee extensors in healthy young individuals (31). Following intense muscle-damaging exercise, local HT was also shown to accelerate the recovery of muscle fatigability when compared with a sham intervention (30).

Although the positive impact of repeated HT on muscle size and function is increasingly well documented, some studies indicate that local or whole body heating does not boost or may possibly impair the adaptations to other hypertrophic stimuli, including resistance training and overload due to synergist ablation. Frier and Locke hypothesized that heat stress and the consequent activations of HSPs would magnify the hypertrophic response of the plantaris muscle to overload induced by surgical removal of the gastrocnemius muscle in rats (10a). Contrary to their predictions, preexposure to whole body heating (42°C, 15 min) using a heating pad attenuated the gains in muscle mass after 5 and 7 days of overload. Unfortunately, the animals received only a single HT treatment 24 h before undergoing the surgical ablation surgery. As the effects of HT on muscle mass depend on the frequency of exposure (13), it is unclear whether similar findings would be obtained if HT were applied repeatedly throughout the overload period. Stadnyk et al. (56) reported that local thigh heating using an electric pad during and after leg resistance exercise for 12 wk did not augment training-induced hypertrophy or the improvements in muscle strength. However, the majority of participants reported improved comfort and recovery and reduced strain during exercise with local HT, thus suggesting that this strategy could potentially improve adherence to structure exercise regimens (56).

Early efforts to unravel the mechanisms by which HT elicits increases in muscle mass focused on calcineurin, a serine/threonine phosphatase that has been shown, in some studies, to promote myofiber hypertrophy (9, 54). Kobayashi et al. (32) reported that a single session of whole body HT in rats increased the expression of calcineurin in both the slow-twitch soleus muscle and the fast-twitch extensor digitorum longus in rats. Most important, the increase in soleus muscle mass following HT was partially suppressed by the calcineurin inhibitor cyclosporine A. As calcineurin is activated by elevations in intracellular Ca²⁺, this study prompted the notion that heat stress may trigger myoplasmic Ca²⁺ accumulation (32). Indeed, there is evidence that heat stress promotes an increase in intramyocyte calcium concentration through the activation of transient receptor potential vanilloid 1 channel (TRPV1) (26, 44) and possibly because of an increase in Ca²⁺ from the sarcoplasmic reticulum (60). Regardless of the exact causes, the increase in intracellular calcium may serve as a key signal not only to activate calcineurin, but also a number of other pathways involved in the regulation of muscle mass, mitochondrial biogenesis, and muscle glucose transport. For example, Obi et al. (45) recently showed that exposure of mouse myoblast cells to 42°C for over 30 min increased the phosphorylation level of protein kinase C, which is activated by Ca²⁺ and has been implicated in the regulation of muscle glucose transport.

Particular attention has been devoted to the impact of heat stress on the activation of the mechanistic target of rapamycin complex 1 (mTORC1). This highly conserved serine/threonine kinase protein complex regulates protein synthesis by phosphorylating ribosomal protein S6 kinase 1 (p70S6K) and eIF4E-binding protein (4E-BP). In their seminal report, Uehara et al. (59) demonstrated that the increase in soleus muscle mass following whole body HT was preceded by increased p70S6K Thr³⁸⁹ phosphorylation in rat skeletal muscle, which is indicative of increased mTORC1 activity. A number of studies in rodents (47, 58, 62) and one report in humans (29) have since confirmed these observations and helped cement the notion that the activation of mTORC1 is a hallmark response to HT and a potential mechanism underlying the hypertrophic response to this therapy. Of note, it has been recently shown that the TRPV1-mediated increase in intracellular Ca²⁺ levels activates mTOR and subsequent muscle hypertrophy (27). Conceivably, the aforementioned heat-induced myoplasmic Ca²⁺ accumulation may be one mechanism by which this pathway is activated following exposure to HT.

In addition to stimulating anabolic signaling, emerging evidence indicates that HT may influence the regulation of muscle mass by suppressing protein degradation and mitochondrial clearance. Yoshihara et al. (63) reported that repeated HT in a heat chamber (~41°C for 30 min/day) during 7 days of hindlimb unweighting reduced calpain autolysis and myofibrillar protein ubiquitination and attenuated atrophy in rats. Ohira et al. (46) showed that hindlimb immersion in a warm water bath (~42°C, 30 min/day for 7 days) following denervation in rats reduced the expression of atrogin-1, a muscle-specific ubiquitin ligase that is highly expressed during muscle atrophy, and reduced the abundance of ubiquitinated proteins. In a similar model of denervation induced by sciatic nerve transection in mice, daily HT in a heat chamber (40°C, 30 min/day for 7 days) suppressed autophagy-dependent mitochondrial clearance and the concomitant atrophy (57). These later findings in a rodent model of atrophy were recently replicated in humans. Hafen et al. (17) reported that daily local heat stress for 2 h using pulsed shortwave diathermy prevented the loss of mitochondrial proteins and respiratory capacity during 10 days of single-leg immobilization in young adults. Altogether, these recent studies lend strong support to the notion that HT may be a practical strategy to counteract the detrimental effects of skeletal muscle disuse.

MITOCHONDRIAL BIOGENESIS AND FUNCTION

Chen and co-workers were among the first to examine the impact of heat stress on skeletal muscle mitochondria (6). These authors used a heating pad to increase the core body temperature of anesthetized rats to 41°C for 15 min. Analysis of the gastrocnemius muscle sampled 24 h after the treatment revealed a significant increase in the activity of mitochondrial respiratory chain complexes. When compared with untreated controls, the activity of complex I (NADH-ubiquinone oxidoreductase) and complex II/III (succinate-ubiquinone/ubiquinol-cytochrome c reductase) increased by 43 and 28%, respectively, in the muscles of animals exposed to HT (6). These findings were later shown not to be unique to skeletal muscle. Sammut et al. (52) reported that the enzyme activities of complexes I, IV, and V were substantially elevated in mitochondria isolated from the heart of rats subjected to a single bout of whole body HT.

More than a decade after the foundational studies that showed the positive impact of HT on mitochondrial enzyme activity, Liu and Brooks (38) began deciphering the molecular events that mediate the mitochondrial adaptations to HT. Using C2C12 myotubes as an experimental model, these authors showed that heat stress (40°C for 1 h) upregulates the activity of AMP-activated protein kinase (AMPK) and one of its transcriptional targets, peroxisome proliferator-activated receptor γ-coactivator 1α (PGC1α) (38). This unique mediator of mitochondrial biogenesis regulates the coordinated expression of mitochondrial proteins encoded in the nuclear and mitochondrial genomes. Accordingly, exposure of C2C12 cells to HT was also shown to promote the expression of transcription factors necessary for the coordination of nuclear-mitochondrial gene expression (38). Most importantly, episodic exposure to HT for 5 days increased the levels of several oxidative phosphorylation proteins, as well as mitochondrial DNA content (38).

The groundwork laid by Liu and Brooks (38) propelled a series of studies in both rodents and humans aimed at examining the effects of repeated HT on mitochondrial content and function. Tamura et al. (58) reported that chronic whole body HT (40°C, 30 min/day, 5 days/wk) increased mitochondrial enzyme activity and respiratory chain protein content in mouse skeletal muscle. In humans, Hafen et al. (18) recently showed that local thigh heating using pulsed shortwave diathermy for 2 h daily over six consecutive days augmented maximal coupled and uncoupled respiratory capacity, increased the content of respiratory chain complexes I and IV, and increased expression of PGC1α. In agreement with earlier findings in C2C12 myotubes (38), local heating also caused significant elevations in the phosphorylation of AMPK (18). Collectively, these results indicate that AMPK activation, presumably through temperature-induced changes in energy turnover (11), may play a pivotal role in mediating the mitochondrial adaptations to HT.

It is worth noting these aforementioned findings of increased mitochondrial content and function following HT are not unanimous. Hesketh et al. (21) found no effect of whole body HT treatment in humans for 6 wk on skeletal muscle mitochondrial density, as assessed using immunofluorescence microscopy. Likewise, 8 wk of repeated local thigh heating had no impact on skeletal muscle citrate synthase activity and respiratory chain protein content in young individuals (31). These inconsistencies may stem from variations between studies in the HT modality (whole body vs. local), the magnitude and duration of exposure to heat stress, and the different techniques and biomarkers employed in the assessment of mitochondrial abundance and oxidative capacity.

GLUCOSE METABOLISM AND INSULIN SIGNALING

The anecdotal report that repeated bathing in a hot tub (30 min/day, 6 days/wk, 3 wk) reduced fasting plasma glucose and reduced glycosylated hemoglobin levels in patients with Type 2 diabetes sparked interest in the effects of HT on glucose homeostasis and insulin sensitivity (23). Building upon these findings, Kokura et al. (33) evaluated the impact of regular exposure to whole body HT in db/db mice, a model of Type 2 diabetes mellitus. Compared with control animals, mice treated with HT (38°C for 30 min, 3 times/wk) for 12 wk displayed a significant decrease in fasting blood glucose and insulin levels, improved responses to glucose and insulin challenges, and a reduction in serum levels of triglycerides and free fatty acids. These findings were later replicated in both mouse (8) and rat (16) models of diet-induced obesity and insulin resistance, thus revealing that HT is a powerful tool to combat insulin resistance and associated metabolic abnormalities.

Building upon these findings in rodents, a few studies were recently performed to investigate the impact of repeated HT on metabolic function in humans. Hoekstra et al. (22) showed that 10 sessions of hot water immersion (39°C for 45–60 min) over a 2-wk intervention period, reduced fasting glucose and insulin concentrations in sedentary, overweight men. Similarly, Ely et al. (10) reported that 30 one-hour hot tub sessions (40.5°C for 60 min) over 8–10 wk reduced fasting glucose and improved glucose and insulin sensitivity in women with polycystic ovary syndrome, a neuroendocrine disorder characterized by marked insulin resistance. The systemic improvement in markers of insulin sensitivity were accompanied by changes in insulin signaling in subcutaneous adipose tissue samples (10).

The few available mechanistic studies indicate that the long-term effects of HT on glucose homeostasis may stem from the cumulative effects of transient increases in skeletal muscle glucose uptake after each successive HT treatment. Gupte et al. (16) first showed that a single bout of whole body HT (41°C for 20 min) improved insulin-stimulated glucose uptake in the extensor digitorum longus muscle of rats. Koshinaka et al. (34) extended these findings by showing that the increase in glucose uptake in isolated muscles is temperature-dependent. These experiments in isolated muscles revealed that the heat-induced increase in glucose uptake is not solely the result of increased glucose delivery to the muscle, but likely stems from a direct effect of temperature on glucose transport across the muscle-cell surface or changes in intramyocellular metabolism (16, 34). Using the isolated epitrochlearis muscle as an experimental model, Goto et al. (11) made unique insights into the possible molecular mechanisms that mediate the effects of heat stress on glucose transport. Indeed, these authors showed that the increase in glucose uptake following a brief exposure to heat stress was abrogated after inhibition of glucose transporters (GLUTs) with cytochalasin B, as well as after blockade of AMPK signaling by dorsomorphin (11). On the basis of these findings, these authors speculated that increased AMPK activity upon exposure to heat stress may facilitate glucose transport by promoting the translocation of GLUT4 transporters (11). This interesting hypothesis needs to be further explored, particularly in human skeletal muscle.

CONCLUSIONS AND FUTURE DIRECTIONS

Although still in its infancy, the understanding of the physiological basis of HT has evolved in the past decade, and it is increasingly clear that skeletal muscle remodels substantially in response to repeated exposure to heat stress. The documentation that HT enhances muscle strength and promotes capillary growth and mitochondrial biogenesis in healthy skeletal muscle indicates that this therapeutic tool may prove useful for the rehabilitation of individuals with chronic disability and muscle weakness. This is particularly true for the management of muscular dystrophies, which has been limited by the lack of noninvasive treatment modalities. Nonetheless, the translation of our basic knowledge to the clinical setting must be accompanied by efforts to identify the optimal treatment characteristics, including duration and temperature that magnify the benefits. Only a handful of studies in rodents have been performed to identify how temperature influences the outcomes to repeated HT, and no direct comparisons have been made to explore potential differences in the adaptations to local versus whole body HT modalities. The answers to these questions will provide a solid framework for clinical trials to examine the effects of HT on skeletal muscle function in diseased populations.

GRANTS

Support for this work was provided by the American Heart Association (16SDH27600003), the National Institutes of Health (1R21AG053687-01A1), the Indiana Clinical and Translational Science Institute, and the Showalter Trust Research Award.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

K.K. and B.T.R. conceived and designed research; K.K., T.P.G., and B.T.R. performed experiments; K.K. and B.T.R. analyzed data; K.K., T.P.G., and B.T.R. interpreted results of experiments; K.K. and B.T.R. prepared figures; K.K. and B.T.R. drafted manuscript; K.K., J.C.M., T.P.G., and B.T.R. edited and revised manuscript; K.K., J.C.M., T.P.G., and B.T.R. approved final version of manuscript.