Cryotherapy: Are we freezing the benefits of exercise?^*

* This article was commissioned by Toby Mündel, Discovery Editor.

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We have published a series of articles on the acute and chronic effects of cold water immersion on molecular responses and adaptations in skeletal muscle after exercise.^1-3 These studies were based on two key tenets: (i) cold water immersion reduces inflammation in musculoskeletal tissues and (ii) regular cold water immersion enhances post-exercise recovery and resilience, thereby leading to greater adaptations to training. The first of these tenets is supported by pre-clinical studies on the effects of icing or cryopreservation. By contrast, evidence supporting the second tent has been lacking. We therefore designed two systematic and integrated studies to investigate these proposed benefits of cold water immersion in more detail.

The first study involved a randomized controlled trial in which a group of physically active young men strength trained twice a week for three months.³ One half of the group performed cold water immersion after each training session, which involved sitting up to their waist in water at 10°C for 10 min. The other half of the group performed active recovery after each training session, which involved riding on a stationary bicycle at a self-selected low intensity for 10 min. We measured muscle mass using magnetic resonance imaging (MRI) and strength, and collected resting muscle biopsies before and after the 3 months of training. We discovered that although both groups gained muscle mass and strength following training, these gains were significantly smaller in the cold water immersion group compared with the active recovery group. The cross-sectional area of type II (fast-twitch) muscle fibers also increased only in the active recovery group. Collectively, these findings provided the first definitive evidence against the notion that regular cold water immersion enhances adaptations to exercise training.

To understand the mechanisms behind these effects of cold water immersion in more detail, we performed a randomized, cross-over trial. Another group of physically active men completed two sessions of resistance exercise on separate days, using separate legs. After each exercise session, they performed cold water immersion or active recovery (as described above). We collected blood samples at regular intervals, muscle biopsies before exercise and 2, 24 and 48 h after exercise. We analysed the blood samples and muscle biopsies for a range of variables involved in recovery and adaptation to exercise. We discovered that exercise activated kinases involved in the mammalian target of rapamycin (mTOR) signaling pathway, and stimulated satellite cell proliferation. Activation of p70S6 kinase and satellite cell proliferation were significantly attenuated following cold water immersion,³ which likely accounted (in part) for the smaller gains in muscle mass and strength in the training study described above. We then analysed the same muscle samples for factors involved in ribosomal biogenesis. Ribosomal biogenesis is a key preliminary process involved in gene expression. We observed that exercise activated several pre-ribosomal RNAs and signaling proteins that regulate muscle hypertrophy. Once again, these effects were significantly diminished following cold water immersion,¹ providing further mechanistic evidence to explain the findings from the training study. Lastly, we analysed the blood and muscle samples for various inflammatory markers. Exercise induced a robust inflammatory response characterized by infiltration of neutrophils and macrophages, and increased cytokine gene expression in skeletal muscle. There was also a modest increase in plasma interleukin-6 concentration and creatine kinase activity. In contrast with the findings described above, blood and muscle inflammatory markers did not differ significantly between the cold water immersion and active recovery treatments.² These findings offered the first evidence in humans against the traditional concept that cold water immersion provides anti-inflammatory benefits in muscle after exercise.

The fundamental mechanisms by which cold water immersion may reduce the activity of genes, proteins and cells involved in muscle hypertrophy remain unclear. Muscle temperature (recorded 3 cm deep) decreases by 0.01–0.02 °C after 10 min whole body immersion in water at 8°C and 22°C. It then decreases over the next 30 min—most notably after immersion in water at 8°C.⁴ It is possible that this decrease in muscle temperature after cold water immersion reduces rates of metabolism in muscle, thereby suppressing the activity of key genes, proteins and cells that regulate muscle hypertrophy in the post-exercise period. Over time with exercise training, repeated suppression of this activity could reduce muscle growth and strength.

In contrast with the neutral (or in some instances, negative) effects described above, cold water immersion may provide benefits for other aspects of exercise recovery and adaptation (Fig. 1). Firstly, the most consistent effect of cryotherapy after exercise is a reduction in the degree of perceived muscle soreness. Delayed onset muscle soreness after exercise is associated with activation of bradykinin, cyclooxygenase and neurotrophic factors, and sensitization of nociceptors in muscle. Despite extensive supporting evidence for the analgesic influence of cryotherapy, relatively little is known about the neural mechanisms that underpin this effect. Hand immersion in water at 14°C induces a rapid but brief decrease in sympathetic nervous system activity to skeletal muscle (MSNA). MSNA then returns to normal. By contrast, immersion of the hand in water at temperatures ≤7°C increases MSNA. Increases in MSNA during cold water immersion are likely due to an increase in the firing rate of high threshold, nociceptive nerve fibers. Icing of the ankle (to reduce skin temperature to 10°C) reduces nerve conduction velocity, and this is associated with an increase in pain threshold and pain tolerance. These analgesic effects may be mediated through cold-induced activation of transient receptor potential cation channel M8 receptors present within skin nociceptive nerve fibers.

Figure 1. Overview of the physiological and molecular effects of cold water immersion.

Secondly, by reducing body temperature, cold water immersion may decrease thermal demands and increase heat storage capacity. Ultimately, these effects may result in less central fatigue, lower ratings of perceived exertion and better recovery from exercise.⁵ Thirdly, by reducing limb and skin blood flow, cryotherapy may also increase central venous pressure and central blood volume. These effects may result in less cardiovascular strain, less limb swelling, increased delivery of oxygen to muscle and greater cardiac parasympathetic activity. All of these cardiovascular responses may translate to greater recovery following exercise.⁵

Lastly, cold water immersion has the potential to activate mediators of mitochondrial biogenesis in muscle. Cold water immersion on its own is sufficient to increase the gene expression of peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), a master regulator of mitochondrial biogenesis. Cold water immersion combined with aerobic exercise appears to induce additive effects on the expression/activity of PGC-1α and other mediators of mitochondrial biogenesis such as p38 mitogen-active protein kinase and 5' AMP-activated protein kinase (AMPK) and aerobic enzymes.⁵ Although these molecular responses to cold water immersion are potentially beneficial, no research has examined whether regular cold water immersion following endurance training improves endurance performance.

An extensive body of research exists on the physiological effects of cold water immersion. Changes in tissue temperature, limb and skin blood flow and muscle soreness are well documented and supported, whereas some of the secondary effects of cold water immersion remain more speculative. Current evidence indicates that cold water immersion is not universally beneficial for recovery and adaptation to exercise. In particular, regular cold water immersion appears to attenuate muscle adaptations to strength training, whereas it stimulates molecular responses in muscle that may (theoretically) enhance endurance performance. Further research is warranted to understand the physiological effects of cold water immersion in greater detail, and to establish stronger evidence-based prescription guidelines in terms of the optimal temperature, duration, timing and frequency of cold water immersion to promote recovery and adaptation to exercise.

Evidence exists from many pre-clinical and several human studies for the benefits of various forms of heat therapy, including hot water immersion, microwave diathermy, heat pads, steam blankets etc. These treatments are proposed to enhance recovery of muscle function after exercise, minimize muscle atrophy and stimulate muscle growth following immobilization by activating heat shock proteins and mTOR kinases. We currently have a series of studies underway to determine how hot water immersion influences muscle adaptations to strength training, and the molecular mechanisms that underpin these responses. Further work involving humans is needed to investigate whether heat therapy can mitigate the loss of muscle mass and or enhance muscle growth during rehabilitation from musculoskeletal injury.