Physiological Effects of Spaceflight/Unloading and the Mitigating Effects of Flywheel-Based Resistive Exercise

Microgravity (μg) poses unique challenges to a species that evolved entirely within a load-bearing eugravitational environment. Numerous changes occur as humans are exposed to μg that have far-ranging effects on their health (Gopalakrishnan et al., 2010). Some even question if long-term manned round trip missions to Mars are even tenable (Hawkey, 2005; Riley, 1999). Adverse changes to health and human physiology were seen post-flight from even the earliest short-duration American and Soviet spaceflights. A stimulus for some adverse changes is the disruption of sufficient mechanical and load-bearing activity to the lower body weight-bearing musculoskeleton. Such changes, and the adverse events anticipated from longer missions, led to the deployment of in-flight countermeasures to combat the detrimental effects of μg. This review summarizes nutritional and physiological changes seen with μg, and then addresses the degree of mitigation attained from spaceflight and μg simulation models with flywheel-based hardware. The use of flywheels to impart mechanical loads helped limit musculoskeletal losses in ground-based μg simulation, which in turn led their use on in-flight hardware now on the ISS.

Since the Skylab missions, space agencies are aware of nutritional concerns seen with μg (Smith and Zwart, 2008). Spaceflight causes fluid shifts that lead to motion sickness, taste and smell pertubations, and an altered hormonal status (Hargens and Richardson, 2009; Matsumoto et al., 2011; Moore et al., 2010; Smith et al., 2013). For instance, μg causes a cephalic body fluid shift at the expense of plasma volume (Hargens and Richardson, 2009; Matsumoto et al., 2011; Moore et al., 2010; Smith et al., 2013). The increase in fluids may change the perception for the aforementioned cephalic sensory stimuli, while the lower plasma volume caused by fluid shifts can elicit higher blood concentrations for some hormones. Spaceflight analogs induce physiological losses that typically increase with the longer periods of unloading (Baldwin et al., 1996; Caruso et al., 2005b; Zwart et al., 2012). For instance, bed rest evoked progressively greater weight losses over 30, 60, and 90 days; while unilateral limb suspension evoked progressively greater strength losses after 20 and 40 days of unloading (Caruso et al., 2005b; Zwart et al., 2012). μg typically elicits body weight losses (Matsumoto et al., 2011). Significant body weight decreases occurred in astronauts, with some even exceeding 5% of pre-flight body mass. A similar degree of individual losses also occurred after a 42-day bed rest (Blanc et al., 1998). Body mass losses are exacerbated by other factors, such as losses in appetite (Stein, 2000). Adequate nutrition may help address some of the adverse effects seen with μg and abate the energy deficits caused by in-flight exercise (Matsuo et al., 2012; Parmar et al., 2015; Smith and Zwart, 2008). Actual energy consumption on early spaceflights was low, while ISS missions had crewmembers routinely eating at 90% or above their recommended intakes, which maintained body mass (Smith et al., 2013). Yet higher energy intakes impose added concerns for long-duration missions: when each kilogram of mass must be accounted for during takeoff and storage, how much of this valuable space must be dedicated to foodstuffs to keep astronauts healthy? Once a balance between food intake, energy costs, and the impact exercise has on weight loss are found, only then can optimum in-flight countermeasures to weight loss be devised (Matsuo et al., 2012).

Relationships between exercise in μg and body mass losses are paradoxical, because while exercise abates muscle mass and strength deficits, the resultant energy costs hasten weight loss (Matsomoto et al., 2011; Stein, 2000; Wickman et al., 2011). Unfortunately, when in-flight exercise is deployed, the resultant energy costs are not always accounted for. Human metabolic rates rise sharply in μg (Matsuo et al., 2012; Stein, 2000; Wickman et al., 2011). In-flight peak and average energy costs for extravehicular activities of 500 and 200–250 kcal/hour, respectively, were reported (Stein, 2000; Whittle, 1979; Wickman et al., 2011). A 71-kilogram astronaut has an estimated in-flight energy expenditure of 2938 kcals/day, which entails an allowance for one hour of exercise at a metabolic cost of 490 kcals (Wickman et al., 2011). With higher metabolic rates, in-flight accrual and removal of body heat is another health concern, as post-flight hyperthermia is common (Convertino and Tsiolkovsky, 1990). Sweat rates decline with longer flights, which increases the thermal stress to crewmembers (Convertino and Tsiolkovsky, 1990). For instance, 14 days of bed rest, with exogenous acetylcholine administration before and after the intervention, saw a significant average decline in sweat rate of 33% versus prebed rest values (Crandall et al., 2003). The degree of dehydration seen with 14 days of μg approximates a 10% loss in plasma volume (Ogawa et al., 2009). Submaximal cycle ergometery tests done after 115 days of μg produced a significant average decline in sweat rate of 75% versus pre-flight values (Fortney et al., 1998). Sweating in μg forms a film over the skin that impedes convective heat loss, which can impair an astronaut's ability to perform mission objectives (Convertino, 1990; Fortney et al., 1998). The higher thermal stress from elevated metabolic rates is compounded when exercise is done in μg.

Successful in-flight exercise requires they impose little increase to metabolic rates above those that naturally occur in μg. This is made difficult with limited choices in exercise hardware, as well as finite amounts of O₂ and food; in regards to the latter, life support requirements per crewmember and day provide 0.7 kg of dry food in μg (Matsumoto et al., 2011; Matsuo et al., 2012; Wickman et al., 2011). For longer missions, exercise with modest energy costs will reduce demands on ISS food supplies and the costs to replenish such materials (Matsomoto et al., 2007; Matsuo et al., 2012). Presumably the elevated metabolic rates and hyperthermia seen in humans exposed to μg cause higher energy costs for in-flight exercise than when the same types of activity occur on Earth (Matsumoto et al., 2011; Matsuo et al., 2012; Stein, 2000; Stein et al., 1999; Wickman et al., 2011). In-flight aerobic exercise evokes negative energy balances (Dudley et al., 1991) and removal of large amounts of its byproducts (CO₂, heat) poses added concerns. The link between exercise and energy deficits is exacerbated by reduced protein synthesis (Stein, 2000) and the absence of mechanical-loading (Shenkman and Nemirovskaya, 2008) to evoke vast muscle atrophy and strength losses (Fitts et al., 2000; Wickman et al., 2011).

Insufficient energy intakes in μg may deprive crewmembers of essential nutrients, such as minerals and fat-soluble vitamins (Smith and Zwart, 2008; Smith et al., 2013). There is much agreement on the consequences of vitamin deficiencies in an environment where humans are not protected from radiation by the Earth's magnetic fields (Smith and Zwart, 2008; Smith et al., 2013). Vitamins A, D, E, and K are critical to human health. Vitamin D, in particular, had the most pronounced deficiencies from μg, causing NASA to add vitamin D supplements to dietary plans (Smith et al., 2013). Since vitamin D impacts calcium absorption and bone health, it now serves as a nutritional countermeasure. Minerals perhaps most impacted by μg include calcium, phosphorous, and magnesium (Morgan et al., 2012; Smith et al., 2012c). For instance, calcium accrual within unloaded muscle activates calpains to initiate the myofibrillar protein catabolism that contribute to muscle atrophy and strength loss (Shenkman and Nemirovskaya, 2008). Iron also changes, with heme iron leaving microcytic red blood cells and reduced bloodstream levels of transferrin (usually an acute phase reactant), which can lead to some symptoms of mild anemia as iron stores redistribute themselves (Smith and Zwart, 2008). Finally, of critical importance are the vitamin deficiencies seen with megaloblastic anemias, namely folate and B12, which can cause long-term retinal damage and are a critical health issue in μg (Zwart et al., 2012).

The adverse changes humans experience in μg are interrelated to the higher metabolic rates seen with spaceflight. They include hormonal and cardiovascular changes, oxidative damage, musculoskeletal losses. Concerted efforts were undertaken to devise in-flight treatments to address each of these areas. They including limiting energy costs for the American space program's aerobic exercise regimen (Moore et al., 2010), to artificial g induction (Iwate, 2005), to customized devices with the goal of acting as an all-in-one countermeasure (Streeper et al., 2011).

The prototype of the European Space Agency's in-flight device uses two flywheels to impart resistance during seated leg and calf press repetitions. Bed rest studies, 29–90 days in length, assessed the merits of the prototype flywheel ergometer to abate knee extensor mass and strength losses (Alkner and Tesch, 2004a; Alkner and Tesch, 2004b; Tesch et al., 2004). Results showed concurrent workouts on the prototype ergometer preserved knee extensor mass and elicited strength gains up to 7.7% higher than pre-unloading values, while bed rest control subjects who did not exercise had significant mass (−9–18%) and strength (−30–45%) deficits (Alkner and Tesch, 2004a; Alkner and Tesch, 2004b; Tesch et al., 2004). Yet other studies that used to the same prototype flywheel ergometer produced different results (Caruso et al. 2004b; Caruso et al. 2005b). Three groups of subjects underwent 40 days of unilateral limb suspension (Caruso et al., 2004b; Caruso et al., 2005b). Two groups exercised on the ergometer three days per week, while a third served as unloaded controls. The two flywheel ergometer groups also received a capsule dosing assignment; subjects either consumed a placebo (lactose) or 16 mg · day⁻¹ of albuterol with no crossover. Results showed the combined flywheel ergometer-placebo treatment group preserved knee extensor mass, yet over time that group incurred significant (−10%) concentric strength losses over the 40-day unloading period that were less than those for the unloaded controls (Caruso et al., 2004b). Yet subjects who received the combined flywheel ergometer-albuterol treatment acquired significant increases in concentric (+18%) and eccentric (+10%) total work over pre-unloading values (Caruso et al., 2004b). Ankle extensor data from the same three groups showed the combined flywheel ergometer-placebo treatment led to significant intra-group (~−13–15%) eccentric strength losses over 40 days (Caruso et al., 2005b). Yet subjects who received the flywheel ergometer-albuterol treatment had significant eccentric strength (+23–26%) increases over the 40-day unloading period (Caruso et al., 2005b). More than one reason may account for differences in the flywheel-only outcomes for the 40-day trial and bed rest studies. Motivation levels, which in part resulted from differences in the study designs, may account for much of this discrepancy. For the unilateral limb suspension study, subjects were double-blinded to the capsule assignment and may have led some to erroneously believe they could rely on albuterol's ergogenic effect to abate strength losses. Other studies (Alkner and Tesch, 2004a; Alkner and Tesch, 2004b; Tesch et al., 2004), where only one treatment was administered, subjects knew they must rely solely upon the ergometer to maintain muscle mass and strength, and thus may have been more motivated for workouts.

Prior research questioned if in-flight hardware offered a mechanical loading stimulus of sufficient intensity to abate bone losses (Cavanaugh et al., 2005; Schneider et al., 2003; Shackelford et al., 2005). Due to its ability to abate muscle mass and strength losses in ground-based trials, research assessed the merits of the prototype flywheel ergometer to mitigate bone deficits. A 90-day bed rest study examined subjects concurrently assigned to: 1) prototype flywheel ergometer workouts done every 2–3 days, 2): pamidronate therapy to block bone resorption, or 3): a control (no exercise or drug) condition with no crossover (Rittweger et al., 2005). Results showed ergometer workouts concurrent to bed rest abated calf cross-sectional area losses, while tibial diaphyseal and epiphyseal bone mineral content deficits were abated when pamidronate was used as a countermeasure. Each treatment was only partially mitigated bed rest-induced lower leg losses, and the mechanical loading from the prototype ergometer was thought essential to bone health (Rittweger et al., 2005). Due to the merits of combined prototype ergometer-albuterol administrations on muscle strength, this same treatment was also assessed for its ability to abate unloading-induced bone losses (Caruso et al., 2004a). Subjects performed 40 days of unilateral limb suspension with their left legs, which otherwise refrained from traditional weight-bearing activity. As subjects performed concurrent workouts on the prototype flywheel ergometer three days · week⁻¹ with their left legs, they either consumed placebo capsules or a 16 mg · day⁻¹ dose of albuterol with no crossover. Before and after the 40-day period bone densitometry quantified left leg changes. Mechanical loading values from the ergometer workouts were also analyzed. A significant time effect (pre > post) occurred for pelvic bone mineral density (−1.95%); this was the first study to see significant skeletal losses from unilateral limb suspension (Caruso et al., 2004a). Those in the combined flywheel ergometer-albuterol group incurred significant bone mineral content gains to their unloaded leg and a trend (+2.9%) for higher muscle mass, while the flywheel ergometer-placebo group produced no change to those variables. For the latter stages of the 40-day period, mechanical loads for prototype ergometer-placebo subjects declined significantly (−14%) as compared to intra-group values from the start of unloading period. It was suggested albuterol augmented ergometer workouts to maintain mechanical loads that led to bone mineral content gains to the unloaded leg (Caruso et al., 2004a).

Some unloaded leg variables were maintained throughout the 40-day period in the flywheel ergometer-placebo group (Caruso et al., 2004a). Yet a comparative study showed the ergometer as a sole treatment does not promote bone accretion (Caruso et al., 2005a). With a matched-pairs design, ambulatory subjects were assigned to ten weeks of leg press workouts on the prototype ergometer or a standard leg press device with no crossover (Caruso et al., 2005a). Each group performed identical workout protocols and refrained from all other exercise. The progressive overload incurred by the groups was similar over ten weeks. Significant time (pre < post) effects for concentric knee extensor strength, leg muscle mass, body fat percentage and total fat mass occurred for both groups. Yet bone mineral density data produced group-by-time interactions, as standard resistive exercise evoked significant (+1.2%) gains for both leg and total-body bone mineral density while the prototype ergometer group incurred no change. Bone resorption assays showed insignificant changes. It was concluded, that unlike standard resistive exercise, the mechanical stimuli provided by the ergometer does not impart strains upon bone of a sufficient magnitude and rate to evoke osteogenesis (Caruso et al., 2005a). Study results, whereby it was concluded strain rates impeded bone improvements from workouts done on flywheel-based hardware, illustrate a potential paradox for this exercise modality. While larger flywheels impart greater inertial resistance for a more intense mechanical loading stimulus to muscles, it occurs at the expense of reduced strain rates to bones. Even early papers that extolled the potential of flywheel-based hardware to abate muscle atrophy and strength losses, yet were more reserved in regards to its ability to abate in-flight bone deficits (Berg and Tesch, 1994). Subsequent research results, presented in this paper, appear to support this concern. Less resistance, provided by smaller flywheels, may permit the type of bone strains seen with impulse loading. Best achieved with repetitions done at higher speeds, and defined as the force per unit time, impulse loading may elicit bone mineral density increases over time (Dériaz et al., 2010; Heikkinen et al., 2007).

Unlike the European Space Agency's flywheel-based hardware, NASA produced no prototype of the Advanced Resistive Exercise Device from which bone data were obtained. Yet limited in-flight data was obtained on that device's impact on bone mineral changes during extended (4–6 month) stays aboard The ISS (Smith et al., 2012a). Crewmembers exercised with either the Advanced (n = 5) or Interim (n = 8) Resistive Exercise Devices, the latter's hardware did not have flywheels and imparted comparatively lighter peak loads (Smith et al., 2012a). Data, obtained before and 5–45 days after spaceflights, showed bone mineral content and densities were best preserved in crewmembers who used the Advanced Resistive Exercise Device. For some bone-based dependent variables the inter-group differences were significant despite the modest sample sizes (Smith et al., 2012a). It was reported all crewmembers had nominal vitamin D status before and during spaceflight. It was concluded that with improved nutrition and exercise hardware, spaceflight-induced bone losses could be mitigated (Smith et al., 2012a).