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Journal of Animal Science - 2011 and 2012 Early Careers Achievement Awards

2011 AND 2012 EARLY CAREERS ACHIEVEMENT AWARDS: Metabolic priorities during heat stress with an emphasis on skeletal muscle12


This article in JAS

  1. Vol. 91 No. 6, p. 2492-2503
    Received: Nov 21, 2012
    Accepted: Jan 21, 2013
    Published: November 25, 2014

    3 Corresponding author(s):

  1. R. P. Rhoads 3,
  2. L. H. Baumgard and
  3. J. K. Suagee*
  1. Department of Animal and Poultry Sciences, Virginia Tech, Blacksburg 24061
    Department of Animal Science, Iowa State University, Ames 50011


Environmental heat stress undermines efficient animal production resulting in a significant financial burden to agricultural producers. The reduction in performance during heat stress is traditionally thought to result from reduced nutrient intake. Recently, this notion has been challenged with observations indicating that heat-stressed animals may exploit novel homeorhetic strategies to direct metabolic and fuel selection priorities independent of nutrient intake or energy balance. Alterations in systemic physiology support a shift in metabolism, stemming from coordinated interactions at whole-body and tissue-specific levels. Such changes are characterized by increased basal and stimulated circulating insulin concentration in addition to the ostensible lack of basal adipose tissue lipid mobilization coupled with reduced adipocyte responsiveness to lipolytic stimuli. Hepatic and skeletal muscle cellular bioenergetics also exhibit clear differences in carbohydrate production and use, respectively, due to heat stress. The apparent dichotomy in intermediary metabolism between the 2 tissue types may stem from factors such as tricarboxylic acid cycle substrate flux and mitochondrial respiration. Thus, the heat stress response markedly alters postabsorptive carbohydrate, lipid, and protein metabolism through coordinated changes in fuel supply and use across tissues in a manner that is distinct from commonly recognizable changes that occur in animals on a reduced plane of nutrition. Perhaps most intriguing is that the coordinated systemic, cellular, and molecular changes appear conserved across physiological states and among different ruminant and monogastric species. Ultimately, these changes result in the reprioritization of skeletal muscle fuel selection during heat stress, which may be important for whole-body metabolism and overall physiological adaptation to hyperthermia.


Animal performance is maximized in a narrow thermal range. When the environmental temperature threshold is exceeded, energy and nutrients are diverted from productive processes, such as growth and work, toward maintenance of euthermia. Such shifts in metabolism and alterations in the nutrient partitioning hierarchy decrease animal performance by affecting the extent and composition of BW gain. Thus, heat stress is a significant financial burden in the United States and possibly the largest contributor to reduced animal agriculture income (St-Pierre et al., 2003). The negative effects of heat stress will become even more apparent in the future if climate change continues, as some predict (Thornton et al., 2007), and as the population of the world and, thus, food demand continues to grow in tropical and subtropical regions (Roush, 1994). In addition, genetic improvement programs continue to emphasize production traits, and this may inadvertently decrease heat tolerance because of the relationship between productivity and metabolic heat generation.

There are a variety of direct mechanisms by which a thermal load can reduce or prevent lean tissue accretion and skeletal muscle performance. For example, heat stress alters the endocrine profile and this is primarily characterized by an increase and decrease in catabolic and anabolic hormones, respectively (Morrison, 1983; Beede and Collier, 1986). One of the first noticeable signs of heat stress is reduced nutrient intake that presumably decreases the “heat increment” of feeding. In addition, heat stress is thought to markedly increase maintenance costs (Morrison, 1983; Fox and Tylutki, 1998) as remaining euthermic has an energetic cost. Furthermore, heat can negatively impact cell components directly, such as unfolding and subsequent aggregation of proteins (Lindquist, 1986; Caspani et al., 2004; Roti Roti, 2008). To combat protein damage, hyperthermic animals upregulate a variety of protein chaperone genes (i.e., heat shock proteins) to preserve intracellular protein homeostasis and cytoskeletal and molecular transport (Collier et al., 2008). Once damaged, proteins may be difficult to replace because protein synthesis appears to be particularly impaired by heat (Mondovi et al., 1969). Although extensive productivity research has been conducted, relatively little is known about the metabolic and biochemical changes occurring during heat exposure, especially in skeletal muscle, a highly metabolically active tissue that makes up a majority of animal mass. The aim of this review is to examine the interaction between heat stress-induced physiological modifications and concurrent cellular changes within skeletal muscle that may impinge on animal growth and performance.


Heat stress markedly reduces nutrient intake in growing farm animals and this is a highly conserved response among species. Identifying how much of the decreased productivity is caused by the indirect effect of heat (i.e., reduced feed intake) compared with the direct effect of heat stress on growth is difficult because the composition of tissue accretion is not taken into consideration when measuring gross changes in BW. Therefore, reduced feed intake may appear to explain a portion of the decreased performance in growing animals, but the direct effects of heat may markedly alter the hierarchy of tissue synthesis and fuel selection as discussed below.

Beef Cattle

Advances in management strategies (e.g., providing shade) have alleviated some of the negative impacts of thermal stress on cattle, but production continues to markedly decrease during the summer. Heat-related gain reductions are typically 10 kg, which amounts to approximately 7 d extra on feed (St-Pierre et al., 2003). Growing cattle tolerate higher temperature conditions and exhibit a greater heat strain threshold than lactating cattle, and this enhanced tolerance likely involves 1) increased surface area to mass ratio, 2) differences in feed intake and diet composition causing altered rumen heat production, and 3) reduced overall metabolic heat production on a BW basis. In addition, growing beef cattle will often experience compensatory gain after mild or short periods of heat stress (Morrison, 1983; Mader et al., 2007). Furthermore, the impact of heat stress on reproductive indices is typically not as severe in beef cattle due to the seasonal nature of breeding programs that often occur during the spring in the United States.


The economic losses in the swine industry caused by a sustained thermal load include reduced growth and efficiency, increased health care costs, increased mortality (especially sows and market hogs), inconsistent and reduced market weight, decreased carcass value (increased lipid and decreased protein), and processing issues (i.e., poor carcass fat quality). In addition, lactating sows and young piglets have drastically different thermal neutral zones making management difficult for this stage of production. Interestingly, the fact that pigs reared in heat stress conditions have reduced muscle mass and increased adipose tissue has been documented frequently over the past 40 yr (Close et al., 1971; Verstegen et al., 1978; Stahly et al., 1979; Bridges et al., 1998; Collin et al., 2001). This phenomenon is not unique to pigs, as heat stress also alters body composition similarly in rodents (Schmidt and Widdowson, 1967; Katsumata et al., 1990) and growing poultry (Baziz et al., 1996; Geraert et al., 1996; Yunianto et al., 1997; Lu et al., 2007).

A dramatic reduction in feed intake (up to 50%) is an obvious sign of heat stress and is thought to be primarily responsible for the negative effects heat stress has on pig performance (Collin et al., 2001). It is counterintuitive that heat stress causes a decrease in nutrient intake and depresses growth yet increases carcass lipid accretion and decreases carcass nitrogen content. In thermal neutral conditions, pigs consuming a restricted diet will deposit protein at the expense of lipid accretion (i.e., the carcass lipid to protein ratio decreases, meaning that the carcass becomes leaner) and the quantity of lipid deposited per unit of energy consumed decreases (Le Dividich et al., 1980; Van Milgen and Noblet, 2003; Oresanya et al., 2008). Hence, the reduced feed intake to body composition relationship is exactly opposite in pigs reared in heat stress conditions and is independent of plane of nutrition. Surprisingly, despite its enormous economic impact, little is known about how heat stress directly or indirectly alters metabolism and nutrient partitioning in pigs.


Horses experience a profound 60- to 90-fold increase in metabolic rate during intense exercise whereas humans only experience a 10- to 20-fold increase (Rose et al., 1990; Seeherman and Morris, 1990). The efficiency of converting stored energy into mechanical energy is low (∼20%), and this inefficiency liberates a large amount of thermal energy. Additionally, the surface area to body mass ratio of horses (i.e., 1:100) is much less compared with man (i.e., 1:40), and this places a large demand on thermoregulatory mechanisms to dissipate heat (Hodgson et al., 1993). Furthermore, equine athletes compete in a variety of challenging climates and frequently in environments to which they are not adapted. Exercising non-heat-acclimated horses in warm conditions stresses their thermoregulatory mechanisms and can overwhelm their ability to dissipate heat through evaporative heat loss (Marlin et al., 1996). This has negative health implications for equine athletes, including dehydration, heat stroke, and death (McConaghy, 1994). Furthermore, heat stress also reduces feed intake in horses and this has obvious implications on performance. Thus, the effects of heat stress and prerace climate acclimation has significant implications for equine welfare and performance.

Another factor related to insufficient capacity for evaporative heat losses is anhidrosis, the loss of sweating ability, a condition that can develop in horses of all breeds and ages (Johnson et al., 2010). Anhidrosis most typically develops in horses after relocation from a temperate climate to a hot, humid one and can occur suddenly or after a gradual decline in sweating ability (Jenkinson et al., 2007). The onset of anhidrosis can also occur in horses that have chronically resided in warm climates, and in most of these horses, clinical signs first appear during the warmest summer months (Johnson et al., 2010). Anhidrosis appears to result from degeneration of sweat gland secretory cells and occurs in response to prolonged heat stress (Jenkinson et al., 1989). Although the mechanisms behind secretory cell degeneration are mostly unknown, histologically, secretory cells from anhidrotic horses are flattened instead of cuboidal (Jenkinson et al., 1985; Jenkinson et al., 1989). Furthermore, secretory cells from anhidrotic horses are resistant to β-adrenergic stimulated ion transport (Wilson et al., 2007). Because horses rely on evaporative heat loss from their skin to dissipate the majority of heat produced, anhidrosis occurring in response to prolonged or sudden heat stress negatively impacts the welfare of horses in hot climates.

Cellular Response to Heat Stress

Cell survival during hyperthermia is dependent on a family of proteins known as heat shock proteins (HSP). Members of this protein family are ubiquitously expressed across species and present at low levels under normal conditions but markedly and transiently increase on cellular insult (Li, 1983; Cairo et al., 1985; Ryan et al., 1991; Moseley, 1997). The HSP are grouped based on their molecular weight and AA sequence (Feige and Polla, 1994; Westman and Sharma, 1998) as well as by structure and function (Park et al., 2000). Major HSP in mammalian cells include HSP110, 90, 70, 60, and 27 (Arya et al., 2007), each having separate functions and cellular locations (Feige and Polla, 1994). Classically known as molecular chaperones, HSP bind to unfolded or misfolded proteins and help restore their native conformation (Buchner, 1996; Calderwood et al., 1996; Bouchama and Knochel, 2002). Of these, HSP70 plays a heightened role in cryoprotection (Volloch and Rits, 1999) and is frequently used as a biomarker of cellular stress. Expression of HSP70 is generally considered a good indicator of the magnitude and duration of a thermal stress (Mizzen and Welch, 1988). Ultimately, if damage from heat exposure is not or cannot be repaired, such as that caused by mitotic catastrophe, cell death via heat-induced apoptosis will occur (Roti Roti, 2008). Interestingly, the rapid increase in HSP70 mRNA abundance during acute periods of hyperthermia is associated with altered expression of many enzymes associated with energy metabolism in a skeletal muscle-specific manner (e.g., soleus vs. tibialis anterior) indicating that oxidative muscle fibers may be more susceptible to heat stress than glycolytic muscle fibers (Sanders et al., 2009).

In addition to environmental heat load-induced elevations in core body temperature, exercise that increases body temperatures can also influence HSP expression. For instance, marathon runners maintain a high core body temperature for the duration of a several-hours-long race (Adams et al., 1975; Maron et al., 1977), and to deal with the innate hyperthermic nature of exercise, HSP70 is upregulated (Marfe et al., 2010). This effect also occurs in cardiac blood vessels (Noble et al., 2006; Staib et al., 2007; Milne et al., 2012) and skeletal muscle fibers (Noble et al., 2006; Silver et al., 2012) from rats and humans (Morton et al., 2006) exercised in thermoneutral conditions. When ambient temperatures are increased before or during exercise, there is a further influence on HSP expression. In untrained rats, submaximal exercise in a heated environment increased HSP70 expression further than that observed in rats exercised in thermoneutral conditions (Kim et al., 2004). Similarly, heat stress before exercise significantly increased skeletal muscle fiber HSP70 expression in rats (Silver et al., 2012) and cool weather-acclimated lizards (McMillan et al., 2011). Consequently, the HSP machinery is incredibly sensitive to both exogenous and internal heat production and in unacclimated individuals, the effects of environmental heat stress and exertional heat stress on the magnitude of the HSP response are additive. However, in contrast to the effects of acute heat stress on the HSP response to exercise, heat acclimation blunts exercise-induced HSP expression. For example, basal circulating leukocyte HSP72 expression was increased by heat acclimation but not by exercise in heat-acclimated men (Magalhães et al., 2010). Because exercising in the heat can further increase core body temperatures, it is unknown why the HSP response to exercise is blunted in heat-acclimated individuals. The role of HSP to provide thermal protection during and after exercise may provide clues on how adaptation influences productivity in environmental heat-stressed farm animals.


Protein Metabolism

Heat stress affects postabsorptive protein metabolism and this is grossly illustrated by changes in the quantity of carcass lean tissue in a variety of species (Schmidt and Widdowson, 1967; Close et al., 1971; Lu et al., 2007). Muscle protein synthesizing machinery and RNA and DNA synthetic capacity are reduced by environmental hyperthermia (Streffer, 1982). Skeletal muscle, in particular AA, is mobilized during periods of inadequate nutrient intake or disease to provide substrates in support of energy metabolism. During heat stress conditions, evidence indicates that skeletal muscle is broken down; however, it is not clear if this is a result of catabolism or heat-induced muscle damage and proteolysis (Table 1). We and others have demonstrated that heat-stressed pigs (Pearce et al., 2013), cows (Shwartz et al., 2009), and heifers (Ronchi et al., 1999) have increased plasma urea nitrogen concentrations compared with thermoneutral controls. Plasma urea nitrogen can sometimes be difficult to interpret because it originates from at least 2 sources, depending on species: inefficient rumen ammonia incorporation into microbial protein or hepatic deamination of AA either from the diet or mobilized from skeletal muscle. A better circulating indicator of muscle breakdown is either 3-methyl-histidine or creatine, both of which are increased in heat-stressed poultry (Yunianto et al., 1997), rabbits (Marder et al., 1990), pigs (Pearce et al., 2013), lactating cows (Schneider et al., 1988b), and exercising men (Febbraio, 2001). Additional evidence indicating heat stress directly affects protein metabolism is decreased milk protein levels from heat-stressed cows (Rhoads et al., 2009; Shwartz et al., 2009) and it appears α and β casein synthesis is most susceptible (Bernabucci et al., 2002). The reduction in protein synthesis combined with increased indications of muscle breakdown during heat stress is perplexing because increased plasma insulin, typically observed during heat stress (Fig. 1), normally prevents muscle catabolism.

View Full Table | Close Full ViewTable 1.

The effects of heat stress on plasma metabolites in various species

Metabolite Response Species
Creatine Increase Rabbits (Marder et al., 1990), sheep (Bell et al., 1989), and cows (Schneider et al., 1988a; Abeni et al., 2007)
3-Methyl histidine Increase Rabbits (Marder et al., 1990), chickens (Yalcin et al., 2009), pigs (Pearce et al., 2013), and cows (Schneider et al., 1988a; Kamiya et al., 2006)
Urea Increase Chickens (Yalcin et al., 2009)1, rabbits (Marder et al., 1990), steers (O’Brien et al., 2010), heifers (Nardone et al., 1997; Ronchi et al., 1999), and cows (Kamiya et al., 2006; Abeni et al., 2007; Settivari et al., 2007; Shwartz et al., 2009; Shehab-El-Deen et al., 2010; Wheelock et al., 2010)
No change Sheep (Bell et al., 1989) and chickens1(Lin et al., 2006)
Lactate Increase Pigs (Hall et al., 1980), humans (Fink et al., 1975; Kozlowski et al., 1985), and dogs (Kozlowski et al., 1985)
1Urate and uric acid
Figure 1.
Figure 1.

Model of metabolic fuel use in skeletal muscle during a low plane of nutrition (top panel) or heat stress (bottom panel). During a low plane of nutrition (in thermoneutral conditions, top panel) circulating concentrations of insulin and glucose are reduced whereas plasma fatty acids (FA) are elevated. The myocyte is geared to use FA for energy and circulating glucose use is spared. Activation of the beta-adrenergic receptor (βAR) facilitates glycogenolysis and the release of glucose-1-phosphate (G-1-P). During heat stress conditions, despite a low plane of nutrition, circulating insulin is elevated and plasma FA concentration is reduced. Presumably the myocyte has a reduced capacity to use FA for energy and must rely on glucose (circulating and (or) glycogen) for energy needs. Transported glucose is converted to glucose-6-phosphate (G-6-P) and enters glycolysis. Because of elevated pyruvate dehydrogenase kinase 4 (PDK4) and the corresponding decreased activity of the pyruvate dehydrogenase complex (PDH), substrate flow into the tricarboxylic acid cycle (TCA) is diminished and the cell relies on glycolysis. Lactate efflux increases via pyruvate conversion due to increased lactate dehydrogenase activity (LDH) and likely travels to the liver to serve as a substrate for gluconeogenesis. Hypoxia-inducible factor (HIF-1) may increase PDK4 and LDH during heat stress. An increase in mitochondrial damage and(or) reduced components of the electron transport chain (ETC) would support the increased reliance on carbohydrate and glycolysis for energy. In the diagram, differential substrate and pathway use are portrayed by altered font sizes and line weights.


Carbohydrate Metabolism

Heat stress appears to alter cellular energetics, and these metabolic adaptations to a heat load likely occur to increase survival probability. Lee and Scott (1916) hypothesized that shifting substrate use in skeletal muscles is necessary to decrease metabolic heat production. This early report indicated that acute heat stress caused hypoglycemia in cats, an aspect originally thought to be the reason for reduced worker/laborer productivity during warm summer months. More recently, extensive research has shown increased reliance on intramuscular carbohydrates during exercise in warm conditions compared with the same intensity exercise in cooler environments (Fink et al., 1975; Nielsen et al., 1990; Romijn et al., 1993; Kanaley et al., 1995; Hargreaves et al., 1996; Jentjens et al., 2002). Additionally, muscle lactate accumulation is reported in humans (Febbraio et al., 1994a,b; Hargreaves et al., 1996; Gonzalez-Alonso et al., 1999) and dogs (Kozlowski et al., 1985) whereas reducing the heat load during exercise decreases muscle glycogenolytic rates and carbohydrate oxidation (Kozlowski et al., 1985; Febbraio et al., 1994a,b; Gonzalez-Alonso et al., 1999), all of which indicate that glycolytic metabolism is increased during exercise in the heat. Ultimately, it appears that heat stress increases glucose use by skeletal muscle, and because skeletal muscle is responsible for the majority of glucose disposal (DeFronzo, 1992), small changes in its fuel efficiency can have large impacts on whole-body nutrient flux.

The liver plays a central role in whole body nutrient partitioning by coordinating the fate of exogenously and endogenously derived nutrients. During periods of heat stress, hepatic glucose output increases as a result of increased glycogenolysis (Febbraio, 2001) and increased gluconeogenesis (Collins et al., 1980). Hepatic glucose production typically decreases after ingesting carbohydrates; however, exogenous sugars are unable to blunt heat stress-induced liver glucose output (Angus et al., 2001). In addition, human athletes consistently have increased hepatic glucose production and whole body enhanced carbohydrate oxidation at the expense of lipids (Fink et al., 1975; Febbraio, 2001; Jentjens et al., 2002). Hepatic pyruvate carboxylase gene expression, a rate-limiting enzyme controlling lactate and alanine entry into the gluconeogenic pathway, is increased during heat stress in multiple animal models (O’Brien et al., 2008; Wheelock et al., 2008; White et al., 2009; Rhoads et al., 2011) and in hyperthermic rodents the contribution of lactose to gluconeogenesis increases (Collins et al., 1980; Hall et al., 1980). We have also demonstrated that ruminant hepatic glucose output is not compromised and that the hepatic glycogenolytic responsiveness to catabolic signals remains unaltered in ruminants (Baumgard et al., 2011) and pigs (L. H. Baumgard and R. P. Rhoads, unpublished data). Collectively, these studies appear to indicate that peripheral tissues increase their reliance on glycolysis and that the ability of the liver to supply glucose to systemic tissues remains intact.

Lipid Metabolism

The effects of heat stress on postabsorptive lipid metabolism have not been thoroughly evaluated. Some production and observational data indicate that heat stress may alter metabolism differently than would be expected based on calculated whole body energy balance. For example, heat-stressed sows (Prunier et al., 1997) and heifers (Ronchi et al., 1999) do not lose as much BW and body condition, respectively, as do their pair-fed thermoneutral counterparts. In addition, carcass data indicate that both chickens (Geraert et al., 1996) and pigs (Collin et al., 2001) have increased lipid retention when reared in heat stress conditions and the heat stress effects in chickens are most pronounced in the abdominal fat depot (Yunianto et al., 1997). We and others have demonstrated that basal plasma NEFA concentrations, a product of adipose lipolysis and mobilization, are typically reduced in heat stress sheep and cattle despite marked reductions in DMI (Sano et al., 1983; Ronchi et al., 1999; Shwartz et al., 2009) and especially when compared with pair-fed thermoneutral controls (Rhoads et al., 2009). Furthermore, we have recently demonstrated that heat stress cows have a blunted (compared with pair-fed thermoneutral controls) NEFA response to an epinephrine challenge (Baumgard et al., 2011). These observations agree with rodent results indicating heat stress reduces in vivo lipolytic rates and in vitro lipolytic enzyme activity (Torlinska et al., 1987). The changes in carcass composition, blood lipid profiles, and lipolytic capacity are surprising because heat stress causes a well-described increase in stress and catabolic hormones (e.g., epinephrine, cortisol, glucagon; Beede and Collier, 1986).

The aforementioned changes in lipid metabolism may be the result of increased insulin concentrations and/or enhanced insulin sensitivity because insulin is a potent lipogenic and antilipolytic hormone (Vernon, 1992). In fact, despite the marked reductions in DMI, heat stress increases insulin sensitivity in rodents (DeSouza and Meier, 1993) and basal insulin concentrations in rodents (Torlinska et al., 1987), a hyperthermic porcine model (Hall et al., 1980), growing steers (O’Brien et al., 2010), and lactating cows (Itoh et al., 1998). In addition, heat stress sheep (Achmadi et al., 1993), growing cattle (O’Brien et al., 2010), and lactating cows (Wheelock et al., 2010) have an increased insulin response to a glucose tolerance test. Collectively, the available data indicate that heat-stressed animals have a limited ability to mobilize adipose tissue and, thus, are unable to maintain mechanisms necessary to support the metabolic flexibility of fuel selection.

Mitochondrial Function

Normally, flux through the tricarboxylic acid (TCA) cycle is dictated by oxygen availability, and during rest and low-intensity exercise, the majority of ATP is generated by oxidative phosphorylation. It was traditionally thought that only during hypoxia does the percentage of ATP generation from glycolysis increase (Kim et al., 2006). However, heat stress reduces acetyl-CoA flux through the TCA cycle, even in the absence of hypoxia. During heat stress, pyruvate dehydrogenase kinase 4 (PDK4) mRNA in skeletal muscle is increased, a finding we have observed in rodents (Sanders et al., 2009), pigs (Won et al., 2012), and ruminants (O’Brien et al., 2008). Pyruvate dehydrogenase kinase 4 inhibits the pyruvate dehydrogenase (PDH) complex that controls the flux of glucose carbons through the TCA cycle and is responsible for the irreversible conversion of pyruvate to acetyl-CoA. The PDH complex is covalently modified by PDK4, which inactivates PDH, and by pyruvate dehydrogenase phosphatases, which activate PDH (Harris et al., 2002). The activity of PDK4 and pyruvate dehydrogenase phosphatases is regulated at the transcriptional level by intracellular energy status, metabolism intermediates (i.e., acetyl-CoA and NADH), transcription factors, and hormones such as cortisol and insulin (Sugden and Holness, 2006). Furthermore, circulating lipopolysaccharide is frequently increased due to heat-induced gastrointestinal tract damage (Gathiram et al., 1988; Hall et al., 2001; Bouchama and Knochel, 2002; Baumgard and Rhoads, 2013), and this inhibits muscle PDH via 2 pathways: directly via tumor necrosis factor-α production and indirectly via the nuclear factor-κ B pathway (Alamdari et al., 2008). The regulation of PDH appears to be at the level of PDK4 because PDH protein abundance in skeletal muscle does not differ between environments; however, abundance of phosphorylated (inactive) PDH were increased by exposure to single and multiple heat loads (Sanders et al., 2009). Further evidence indicating that glycolysis is increasing and TCA cycle flux is decreasing during heat stress is the increased ratios of lactate to pyruvate (Elsasser et al., 2009) and NADH to NAD+ (Streffer, 1988). Within the tibialis anterior, a predominantly glycolytic skeletal muscle, lactate dehydrogenase (LDH) A mRNA abundance was increased whereas expression of LDH isoforms in the soleus, a predominantly oxidative muscle type, was not affected by heat (Sanders et al., 2009). This is indicative of an increase in lactate production capacity by type II but not type I skeletal muscle in response to a heat load.

Reduced oxidative glucose metabolism during heat stress may also be the result of events stemming from mitochondrial dysfunction and intracellular reactive oxygen species (ROS) generation. It is widely accepted that mitochondrial respiration is the primary source of ROS (Cadenas and Davies, 2000; Turrens, 2003), with 0.2% of consumed oxygen converted into superoxide in the normal state (St-Pierre et al., 2002). Redox centers of the 4 enzyme complexes within the electron transport chain can form reactive oxygen species by reducing molecular oxygen to form the superoxide anion; complexes I and III are currently viewed as the main contributors to superoxide formation (Barja, 1999; Genova et al., 2003; Gredilla et al., 2004). Generation of ROS, such as superoxide, can damage proteins, DNA, and lipids (Halliwell and Gutteridge, 1999; Apel and Hirt, 2004) and decrease mitochondrial function (Addabbo et al., 2009). Previous reports indicate that mitochondria may be affected directly by heat stress (Bornman et al., 1998; Davidson and Schiestl, 2001; Qian et al., 2004). Histological analysis of skeletal muscle in a rat heat stroke model indicated mitochondrial abnormalities, denoted as ragged-red fibers, and electron-microscopic observations revealed an increased number and size as well as altered morphology of mitochondria (Hsu et al., 1995). Interestingly, the location of mitochondria from heat-stressed rats was also altered because skeletal muscle expressing ragged-red fibers exhibited mitochondria aggregated within the subsarcolemmal space, indicating an increased energy demand of the plasma membrane due to hyperthermia (Hsu et al., 1995). This may in part be due to the marked increase in skeletal muscle Na/K sodium-potassium adenosine triphosphatase activity during acute heat stress (Pearce et al., 2011). In rat cardiomyocytes, heat stress resulted in swollen mitochondria with broken cristae and low matrix density in addition to decreased ATP content in the myocardium (Qian et al., 2004). Moreover, we examined the effect of heat strain on skeletal muscle during beef cattle adaptation to chronic heat stress conditions using microarray analysis. Interrogation of the microarray data by pathway analysis revealed a dramatic downregulation in the skeletal muscle transcript profile relating to mitochondrial function (Rhoads et al., 2008). Similarly, an acute bout of heat stress in pigs caused a decrease in the expression of mitochondrial transcription factor A, succinate dehydrogenase complex, and cytochrome b genes in skeletal muscle (Won et al., 2012). Because mitochondria are the major source of energy production within most cells, mitochondria damage can impair the ability of a cell to compensate for the increased energy demands (Hubbard, 1990) imposed by environmental stresses and may contribute to increased levels of oxidative stress. Acute heat stress increases antioxidant defenses, including Mn superoxide dismutase gene expression and catalase activity, indicating a potential need to protect myocytes from elevated ROS (Sanders et al., 2010; Selsby et al., 2011). Taken together, increased transcription of PDK4 and the subsequent inactivation of the PDH complex might serve as a mechanism to reduce substrate oxidation and mitochondrial ROS production in an effort to prevent cellular damage during heat stress. From a growth perspective, this strategy may limit energy necessary for anabolic processes and may help explain a portion of the compromised efficiency during elevated temperatures. Regardless, gaining a better understanding of the cellular energy equilibrium during heat stress is necessary to devise mitigating strategies to ameliorate production losses.

Hypoxia-Inducible Factor

An attractive candidate known to shift cellular metabolism toward glycolysis is hypoxia-inducible factor (HIF)-1 (Pouyssegur and Mechta-Grigoriou, 2006). Although most HIF signaling research has focused on oxygen tension, there is growing understanding that HIF is regulated by stressors such as hyperthermia and ROS (Jackson et al., 2006; Horowitz and Assadi, 2010). Heat shock factor (HSF) binds to heat shock response elements in the promoter of target genes (Lis and Wu, 1993; Wu, 1995), including HIF-1α, and therefore regulates its transcription (Chen et al., 2011). Concentrations of HIF-1α protein increase in response to hypoxia (Louapre et al., 2005) and heat (Maloyan et al., 2005). Normal concentrations of oxygen stabilize the enzymes that degrade the α-subunit of HIF-1 (Ivan et al., 2001; Jaakkola et al., 2001); thus, stable HIF-1 is only present during hypoxia. Stable HIF-1α binds to hypoxia response elements in the promoter region of numerous genes involved in glycolysis and angiogenesis (Semenza, 2003; Rocha, 2007). Hypoxia-inducible factor-1α dimerizes with HIF-1β and enhances the expression of glucose metabolism genes, including glucose transporter-1 (GLUT-1; Song et al., 2009; Kihira et al., 2011). Glucose transporter-1 is a non-insulin-dependent transporter that facilitates basal glucose uptake and could contribute to the hypoglycemia typically observed in chronic heat-stressed animals (Baumgard and Rhoads, 2013). Additionally, reports indicate that HIF acts as a metabolic switch for cellular adaptation to hypoxia by increasing PDK expression and downregulating mitochondrial oxygen consumption (Papandreou et al., 2006). Consequently, it appears that HIF may be a key molecular controller orchestrating intracellular fuel oxidation during environmental-induced hyperthermia.


In normal physiological conditions, increased insulin concentrations shift metabolism from fat oxidation to glucose use. This metabolic fuel shift stems from the potent antilipolytic activity of insulin (i.e., it reduces adipocyte NEFA export) and by increasing cellular glucose uptake and key glycolytic enzymes (Carpentier et al., 2005). Despite hallmarks traditionally associated with hypoinsulinemia, such as marked reductions in feed intake, calculated negative energy balance, and rapid BW loss, we have demonstrated that basal and stimulated insulin concentrations are increased in a variety of heat stress animal models (Baumgard and Rhoads, 2013). The increase in insulin, a potent anabolic hormone, during heat stress (an intensely catabolic condition) is seemingly a biological paradox. Reasons for hyperinsulinemia during heat stress are not clearly understood but likely include the key role of insulin in activating and upregulating HSP (Li et al., 2006). Proper insulin signaling/action is strengthened by an effective heat protective response (Geiger and Gupte, 2011). The lack of a NEFA response during heat stress may allow for the increase in circulating insulin as excessive NEFA cause pancreas β-cell apoptosis (Nelson et al., 2002). It is unknown if 1) heat shock response elements are present in the promoter of the insulin gene, 2) stored insulin is stabilized by HSP within the β cell, or 3) there is reduced insulin storage (e.g., increased secretion) during heat stress. A second possibility is decreased hepatic clearance of insulin. The liver is thought to be damaged during heat stress (Das, 2011) and may be less capable of producing insulin-degrading enzyme. Regardless of why, heat stress is 1 of the very few nondiabetic models of which we are aware where nutrient intake is markedly reduced but basal and stimulated insulin concentrations are increased.

The effects of heat stress on insulin-induced glucose uptake remain ambiguous because although we reported that heat stress enhances glucose disposal in lactating dairy cows (Rhoads et al., 2009), we could not replicate the increased glucose disposal after a glucose tolerance test in another trial with lactating dairy cows (Baumgard et al., 2011) or in a trial with growing calves (O’Brien et al., 2010). Reasons for the inconsistencies are not clear but may involve tissue-specific differences in insulin action. We conducted a study designed to examine the acute insulin responsiveness of skeletal muscle during an insulin tolerance test by measuring insulin receptor and thymoma viral proto-oncogene 1 (AKT) abundance as well as AKT phosphorylation (Cole et al., 2011). Although protein abundance of the insulin receptor, insulin receptor substrate, and AKT remained stable between environments, insulin-mediated AKT phosphorylation (activation) tended to decline in pair-fed but not heat stress animals. Thus, aspects of skeletal muscle insulin responsiveness appear to remain intact during heat stress. Although this study only examined a single signaling pathway in skeletal muscle, alteration in insulin responsiveness during heat stress is dependent on a number of variables and likely occurs in a tissue-specific manner. What is consistent among these studies is that heat-stressed animals have a much greater insulin response to insulin secretagogues, as discussed previously. Additional studies are needed to elucidate the role of insulin and corresponding tissue responsiveness on cellular and metabolic adaptations during heat stress.


Current evidence indicates that hyperthermic animals initiate a variety of postabsorptive metabolic changes that are in large part independent of reduced feed intake and whole-animal energy balance. Ostensibly, alterations in nutrient partitioning are adaptive mechanisms used to prioritize the maintenance of euthermia. A key difference between a thermoneutral and a heat-stressed animal in a similar energetic state may lie in the inability of the hyperthermic animal to use “glucose sparing” mechanisms to homeorhetically prioritize performance. An inability to mobilize adipose tissue reduces metabolic fuel options (e.g., NEFA and ketones) creating a “metabolically inflexible” situation where reliance on carbohydrate use and glycolysis is favored. From an animal agriculture standpoint, these survival strategies reduce productivity and seriously jeopardize farm economics.

Although our understanding of heat stress-induced postabsorptive metabolism is growing, many of the basic mechanisms remain unclear. For example, the basis for heat stress signals leading to an increase in circulating insulin is unknown. Moreover, potential differential tissue responsiveness to insulin is elusive although it is presumed that insulin action is necessary for skeletal muscle adaptation but prevents adipose tissue mobilization, especially during periods of enhanced catabolic signals and hypoglycemia. Clearly defining the biology and mechanisms of how heat stress jeopardizes animal health and performance is critical in developing approaches to ameliorate current production issues and is a prerequisite for generating future mitigating strategies to improve animal well-being and performance (growth, reproduction, and lactation) and agriculture economics.




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