Clinical Applications of Iso-Inertial, Eccentric-Overload (YoYo™) Resistance Exercise

In the quest for a viable non-gravity dependent method to “lift weights” in space, our laboratory introduced iso-inertial resistance (YoYo™) exercise using spinning flywheel(s), more than 25 years ago. After being thoroughly tested in individuals subjected to various established spaceflight analogs, a multi-mode YoYo™ exercise apparatus was eventually installed on the International Space Station in 2009. The method, applicable to any muscle group, provides accommodated resistance and optimal muscle loading through the full range of motion of concentric actions, and brief episodes of eccentric overload. This exercise intervention has found terrestrial applications and shown success in enhancing sports performance and preventing injury and aiding neurological or orthopedic rehabilitation. Research has proven that this technique offers unique physiological responses not possible with other exercise hardware solutions. This paper provides a brief overview of research that has made use, and explored the efficacy, of this method in healthy sedentary or physically active individuals and populations suffering from muscle wasting, disease or injury. While the collective evidence to date suggests YoYo™ offers a potent stimulus to optimize the benefits of resistance exercise, systematic research to support clinical use of this method has only begun to emerge. Thus, we also offer perspectives on unresolved issues, unexplored applications for clinical conditions, and how this particular exercise paradigm could be implemented in future clinical research and eventually being prescribed. Fields of particular interest are those aimed at promoting muscle health by preventing injury or combating muscle wasting and neurological or metabolic dysfunction due to aging or illness, or those serving in rehabilitation following trauma and/or surgery.


INTRODUCTION
The National Aeronautics Space and Administration (NASA) and the international space medicine community recognized muscle loss and associated neuromuscular dysfunction following spaceflight as serious concerns decades ago, challenging the prospect of future travels to distant planets. Although it was long known that low intensity aerobic exercise does not produce muscle hypertrophy or increased muscle strength or power, for many years the idea prevailed that any aspect of physical deconditioning, typical of spaceflight, could be attenuated by prescribing in-flight aerobic exercise (Convertino, 1994). In the non-peer-reviewed technical journal Griffin, published in 1990 by the SAAB-SCANIA group, Drs. Dudley and Tesch discussed different tentative solutions, including "bluesky" concepts that could battle space-induced muscle atrophy and dysfunction. Not leaving out pharmacological or nutritional interventions, these authors concluded that resistance exercise presents by far the most attractive solution to cope with and offset neuromuscular dysfunction that occurs with long-term exposure to microgravity. However, lack of (or reduced) gravity forces on a space vehicle, station or distant planet, limits or excludes the use of the vast majority of effective commercial exercise apparatuses. As a consequence, a finite solution regarding exercise hardware and prescriptions to combat such effects in-flight is still not routinely operational.
In addition to being responsible for producing body movement(s), skeletal muscle, by far the largest organ of the human body, plays an essential role as a reservoir for, and regulator of, metabolic and endocrine processes. Hence, preserving muscle and neuromuscular function is critical to health and quality of life (Doherty, 2003). Consequently, muscle loss resulting from spaceflight, but also from aging, disuse, trauma or disease, presents a serious threat to skeletal muscle integrity and health. As resistance exercise serves as the cardinal, and unchallenged, non-pharmaceutical strategy to combat deleterious effects on skeletal muscle function and mass, pursuing highly effective exercise hardware and protocols are warranted. Following the introduction of the iso-inertial YoYo TM technology as a viable and physiologically sound exercise device for space crew (Berg and Tesch, 1994), mounting evidence suggests this solution offers, and mediates, unique physiological responses and benefits beyond what is possible by means of other established resistance exercise interventions (Norrbrand et al., 2008(Norrbrand et al., , 2010(Norrbrand et al., , 2011Cuenca-Fernandez et al., 2015). There is sparse, yet growing evidence that this method also has important clinical applications and could serve geriatric populations and athletes and other patients in need of rehabilitation following muscle wasting or orthopedic/neurological trauma (Greenwood et al., 2007;Onambele et al., 2008;Romero-Rodriguez et al., 2011;Fernandez-Gonzalo et al., 2014c;Sarmiento et al., 2014;Abat et al., 2015;Oliveira et al., 2015;Gual et al., 2016;Fernandez-Gonzalo et al., 2016a). This review covers research, pertinent to clinical applications, which has made use of, and explored the efficacy of, this novel resistance exercise paradigm favoring eccentric overload. Other exercise methods and technologies which offer and emphasize eccentric loading profiles different from "normal" coupled concentric and eccentric action cycles, as in lifting and lowering a weight, or electrically powered devices, have been employed in research and clinical settings. It is beyond the purpose of this paper to review the literature covering the topic of eccentric exercise training. For this, the reader is referred to other excellent reviews (e.g., LaStayo et al., 2003LaStayo et al., , 2014Hedayatpour and Falla, 2015) providing very strong support for eccentric exercise training, including accentuated eccentric loading, as a highly effective, safe and feasible clinical method.

THE EVOLUTION OF ISO-INERTIAL YOYO TM EXERCISE
The birth of the YoYo TM evolved from several pivotal research findings and challenges. First and foremost, there was an urgent quest for a non-gravity dependent method to mimic weight lifting and serving astronauts in space while coping with associated operational, physiological and technical challenges. The confined environment on any spacecraft calls for an exercise apparatus that possesses a small envelope and mass that could readily be dismounted and stowed. Materials selection of the components of any product flown on a spaceship is restricted, as e.g., numerous materials are considered hazardous. Ideally, the exercise modality chosen should not use excess energy, water, O 2, or external power, as supply of these sources is restricted on a spacecraft.
Past research using a motor-driven device had shown that elbow flexor resistance exercise with eccentric actions produced greater increases in muscle strength than exercise using concentric actions (Komi and Buskirk, 1972). Spurred by the results of this particular study and other subsequent observations using exercise(s) emphasizing eccentric actions (Häkkinen and Tesch, 1981), we initiated a series of studies in the late 1980's employing either motor-driven  or weight-loaded resistance exercise (Hather et al., 1991;Dudley et al., 1991a,b) to explore the effects of combinations of coupled eccentric and concentric training programs on muscle size, morphology and metabolism as well as motor function. Collectively, in healthy men and women, constant velocity (i.e., isokinetic) resistance exercise involving eccentric actions produced more robust increases in muscle strength than concentric resistance exercise Tesch, 1990, 1991). However, these changes were accompanied by modest muscle hypertrophy. In contrast, chronic coupled concentriceccentric resistance exercise training with heavy weights, calling for acceleration and deceleration, prompted significantly greater muscle hypertrophy and increases in strength, than training omitting eccentric actions (Hather et al., 1991;Dudley et al., 1991b). Likewise, and regardless of exercise modality, eccentric training carried over to favorable adaptations in concentric modes, whereas concentric actions had less impact on eccentric strength and performance outcomes Tesch, 1990, 1991;Dudley et al., 1991b). It is also noteworthy that rate of improvements and progression in training load over the course of training tended to plateau much earlier when eccentric actions were left out.
To our knowledge, the history of using the inertia of flywheel(s) as a source to provide resistance for muscular work dates back to 1796 when Frenchman Francis Lowndes described a whole-body exercise device based on this principle (Good et al., 1819). While this apparatus was aimed at executing physiotherapeutic exercises, giant scientists and Nobel Prize laureates A.V. Hill and August Krogh and associates independently conducted experiments based on this mechanical principle in the first decades of the twentieth century (Krogh, 1913). However, the pioneer work by these entrepreneurs and scientists, similar to those by investigators in more recent times (Pearson et al., 2001), focused on exploring bioenergetics and mechanics of skeletal muscle, rather than utilizing this tool to offer exercise training.
The paper by Berg and Tesch, published in 1994, reintroduced and described how inertia of a spinning flywheel(s) could be utilized to execute resistance exercise. Again, this work emanated from the quest and challenge of "lifting weights" to serve astronauts on missions in space. Consequently, novel hardware (the YoYo TM Leg Press configuration) was tested and validated by the crew who completed the STS-78 Life Science mission on Space Shuttle Columbia in 1996 . A year earlier, and in preparation for this important spaceflight, eight healthy men were examined over several weeks of bed rest and subjected to YoYo TM exercise testing (NASA, 1996). Subsequent experiments, sponsored by NASA and the European, Canadian, Russian and Japanese space agencies, explored the effects of YoYo TM training on muscle and bone of men and women subjected to various analogs simulating spaceflight (e.g., confinement, bed rest or unilateral lower limb suspension up to 110 days; see below).

THE YOYO TM METHOD
In brief, any apparatus or configuration using the current principle (Berg and Tesch, 1994;Norrbrand et al., 2008) is the resemblance of a reversed children's toy yoyo (hence the trademark YoYo TM ). Pulling, pushing or curling the strap, which is anchored to a pivoting lever arm of the apparatus, a handle attachment, or a harness worn by the trainee (Alkner et al., 2003;Norrbrand et al., 2011), initiates rotation of the fixed shaft, which holds the flywheel(s). The inertia is determined by mass, configuration/profile and diameter of the wheel(s). Once the strap is fully wound off the shaft, the energy imparted and stored in the system pulls the strap back onto the shaft, as the trainee aims at resisting this action, bringing the flywheel(s) to a stop and thus completing a cycle. Unlike in lifting a weight, this unique exercise method ensures accommodated resistance, and provided effort is maximal, optimal muscle loading at any particular joint angle through the entire concentric action. This way, and because there is no "sticking point" (or biomechanical lever issues) involved when performing YoYo TM exercise, energy or work produced exceeds by far what can be attained in the concentric action using gravity dependent free weights. The subsequent eccentric action must then absorb the energy stored in the flywheel(s). Due to the absence of, or minute, frictional force characterizing any YoYo TM system, the energy for the concentric and eccentric phases will be almost identical. However, by delaying and hence performing the breaking action in a very narrow window, the time to dissipate the kinetic energy produced is condensed. This approach results in greater eccentric peak force and power (energy/time). Thus, eccentric "overload" is offered by strategically and intentionally delaying initiation of the breaking action (Figure 1). The protocols employed in the vast majority of studies, referred to in this review, used four sets of seven repetitions using maximal effort and the above strategy, and had volunteers perform this regime either every third day or, alternately, 2 or 3 days weekly.
While the execution of resistance exercise using free weights (e.g., barbell, dumb bell, kettle bell) certainly offers several attractive and versatile features, YoYo TM possesses additional unique attributes facilitating physiological advantages over free weights. Assuming the effort is maximal in the very first repetition of a set and thereafter, all repetitions produce maximal loading through the full range of motion of the concentric action (see above). When lifting a weight for a set to failure, or when using other accentuated eccentric training forms where the load is set, only the last repetition calls for maximal activation, yet only at the angle representing the sticking point. Also, without assisted spotting, free weight exercise cannot readily provide eccentric overload. Similar to when lifting a free weight, but in contrast to what is the case with most commercial weight loaded exercise systems (i.e., weight stacks), there is negligible frictional forces involved in propelling the flywheel(s) of the YoYo TM to accelerate or decelerate the motion. Indeed, the vast majority of commercial weight stack machines inherently produce marked eccentric "under-load" due to excess friction (Dudley et al., 1991b).

ACUTE RESPONSES TO YOYO TM EXERCISE
Similar to other resistance exercise modalities (Dudley et al., 1991a), YoYo TM is performed at a very low metabolic cost (Berg and Tesch, 1994;Caruso and Hernandez, 2002). This is because the long known fact that energy needed to perform an eccentric action is only about one fifth of that required for the concentric action of the same cycle (Fenn, 1924). Hence, populations suffering from, or at risk of, cardiovascular pathologies could benefit from any exercise favoring eccentric actions, and this is certainly advantageous on missions in orbit where energy is to be preserved.
In contrast to running, jumping and hopping activities, characterized by a short-lived eccentric action initiating the stretch-shortening cycle (SSC), any YoYo TM exercise relies on both prolonged eccentric exposure and a brief episode of very high SSC activity (Martinez-Aranda and Fernandez-Gonzalo, 2016). In the world of sports, alpine skiing is unique as the eccentric action critical in making the skis to turn, is executed at a very slow angular velocity (Berg et al., 1995;Tesch, 1995). As an example, and similar to exercise using YoYo TM , the giant slalom calls for greater eccentric than concentric EMG activity.
Studies comparing surface EMG during all-out exercise using weights or weight-stack machines on one hand and YoYo TM in a given exercise task consistently report greater global EMG activity with YoYo TM (Berg and Tesch, 1994;Onambele et al., 2008;Norrbrand et al., 2010). Likewise, in head-tohead comparisons assessing muscle involvement by means of functional magnetic resonance imaging (fMRI), the YoYo TM Supine Squat (Norrbrand et al., 2011) and YoYo TM Leg Press (Berg et al., 1991) produced significantly greater muscle use than the barbell squat. These notions were confirmed in professional FIGURE 1 | Typical smoothed torque values across a set of 7 maximal repetitions of YoYo TM knee extension exercise in young healthy men. Black line denotes torque; gray line denotes knee angle. Typically, torque increases over the initial three repetitions, whereas from the fourth or fifth repetition, peak torque typically decreases due to fatigue. soccer players, who were subjected to acute exercise using four different hamstring modalities (Fernandez-Gonzalo et al., 2016b;Mendez-Villanueva et al., 2016). By employing fMRI analysis, these investigators showed greater involvement of all aspects of the hamstring muscle complex, including agonists, and more substantial individual muscle use with the YoYo TM Leg Curl compared with other established gravity or nongravity dependent hamstring exercise methods examined. The superior efficacy to involve the hamstring muscles substantiates the findings of Tous-Fajardo et al. (2006), who measured EMG activity in twenty rugby and soccer players performing bouts on the YoYo TM Leg Curl. Thus, surface EMG activity of mm. biceps femoris and semitendinosus, most prone to hamstring injury, was significantly higher than EMG measured during maximal voluntary contractions (MVCs) of the knee flexors. Given that any exercise-induced enhancement in muscle signal intensity (T 2 ), assessed by means of fMRI, is proportional to EMG activity (Adams et al., 1992) and work (Jenner et al., 1994), it appears YoYo TM exercise facilitates more substantial muscle involvement than other resistance exercise methods.
Another intriguing effect elicited by the method was reported by Cuenca-Fernandez et al. (2015). Competitive swimmers carried out one bout of 3-4 lunges using either the YoYo TM Squat or barbell 8 min prior to a sprint swim, to determine and compare effects on the post-activation potentiation (PAP) phenomenon (Hodgson et al., 2005). This acute effect, reflected in augmented contractile force, is believed to be due to amplified myosin cross-bridge activation mediated by increased myoplasmic Ca 2+ concentrations. Interestingly, the YoYo TM intervention enhanced neuro-motor performance more than the barbell task. Thus, this acute sole bout had a most significant impact as speed and hence swim sprint performance was improved. The authors attributed this response to the PAP effect.
Altogether, the greater overall load and mechanical stress placed on muscle, eliciting more concentric and as a result more eccentric work, appears to be responsible for the more robust muscle use demonstrated with YoYo TM exercise. Additionally, we speculate other unidentified supraspinal and spinal mechanisms facilitate motor unit recruitment beyond what is conceivable by means of standard weight-loaded exercise or other accentuated eccentric loading forms.

EXERCISE TRAINING BENEFITS IN HEALTHY INDIVIDUALS AND ATHLETES
The premier training study that employed the open-chain knee extensor YoYo TM (12 sessions over 5 weeks) reported increased isometric, concentric and eccentric force or strength accompanied by a 6% increase in quadriceps muscle volume . Taken together with the results of subsequent studies employing similar protocols (Table 1), weekly increases in force production typically exceed 2%. This effect is paralleled by increases in muscle size of ∼1% per week in response to short-term (∼5 weeks) training programs (Seynnes et al., 2007;Norrbrand et al., 2008;Lundberg et al., 2013). Whereas traditional knee extensor weight-stack training shows comparable strength increases (Norrbrand et al., 2008), muscle hypertrophy occurs at a rate that is at least two-fold greater with YoYo TM than with traditional resistance exercise protocols and hardware (Wernbom et al., 2007;Norrbrand et al., 2008). Moreover, 10-20 day YoYo TM training produced significantly increased muscle fascicle length and pennation angle paralleling muscle hypertrophy (Seynnes et al., 2007). Hence, muscle architectural changes may contribute to the early onset of increased force producing capacity. Similar to weight resistance exercise, strength and power increases following YoYo TM chronic exercise training are accompanied by marked neural adaptations evident by increased maximal EMG activity (Seynnes et al., 2007;Norrbrand et al., 2010). This effect is most obvious for eccentric actions and greater with YoYo TM than experienced with exercise using weights (Norrbrand et al., 2008(Norrbrand et al., , 2010. It remains to be shown if such an obvious difference in response results from the unique loading features characterizing YoYo TM exercise. The positive benefits of YoYo TM exercise are manifest in athletes as well. For example, 81 volley-and basketball players examined over 24 weeks had just one weekly bout of 4 sets of 8 repetitions of YoYo TM Squat exercise added to the mandatory conditioning regime. These athletes displayed improved strength and vertical jump performance, and more so than players who did not receive this additional treatment (Gual et al., 2016). Likewise, using the YoYo TM Leg Curl configuration targeting the hamstring muscle group, professional footballers showed improved strength, vertical power and horizontal speed after 10 weeks (1-2 times per week) of training compared with their fellow players who maintained normal strength and power training routines (Askling et al., 2003). Similarly, soccer players subjected to YoYo TM Squat and Leg Curl exercise improved vertical and horizontal power (de Hoyo et al., 2015). This investigative team and others (Martinez-Aranda and Fernandez-Gonzalo, 2016) highlighted the importance of individually identifying and employing the optimal inertia that maximizes performance outcomes. Change of direction (COD) ability is a critical feature in soccer, and almost any other team sport played on turf, wooden floor or ice. Using a multi-task exercise paradigm including the YoYo TM Squat for lateral actions, soccer players were examined before and after training to assess the effects on COD speed (Tous-Fajardo et al., 2016). This proof-of-principle study showed the impact on COD ability was paramount in athletes who were subjected to YoYo TM Squat. Athletes who performed a more conventional strength and speed regime showed no such improvement. Although, the YoYo TM Squat offered by far the most powerful exercise task, the investigators were not able to elucidate the critical stimulus responsible for the markedly enhanced performance.
Collectively, the results to date reveal more robust acute physiological responses, and training-induced neuromuscular adaptations following resistance exercise employing iso-inertial YoYo TM compared with traditional weight training. Hence, employing eccentric overload through this method offers a stimulus that is more potent than that offered by gravitydependent resistance exercise(s). These attributes extend beyond sports performance and might be of even greater significance in populations suffering from neuromuscular dysfunction, metabolic, hormonal or other disorders. Whether the YoYo TM exercise method is superior to other resistance exercise modalities emphasizing eccentric exercise remains to be explored. Nevertheless, cumulated research data and significant anecdotal evidence suggests that the YoYo TM method offers a safe (see below), yet a powerful and highly time-effective strategy to enhance performance, not only in high-caliber athletes but also in sedentary and clinical populations.
The specific mechanism(s) responsible for such seemingly superior adaptations remain to be defined. Nonetheless, the greater overall concentric work and power produced with the method inherently generates more eccentric power, which ought to impact the endpoint training result. Further, it is highly likely YoYo TM exercise relies on greater proprioception and more so than controlled weight lifting (Hedayatpour and Falla, 2015). This may be because each concentric-eccentric cycle calls for high acceleration in the concentric action and deceleration to bring the flywheel(s) to a stop, evoking significant stretch loads and a brief episode of eccentric overload. While these are paramount stimuli to fully activate all motor units, the high force and power production, and the stretch per se, are also fundamental in optimizing skeletal muscle protein synthesis (Tannerstedt et al., 2009;Friedmann-Bette et al., 2010).

COMBATTING CONSEQUENCES OF SPACEFLIGHT, MUSCLE DISUSE, DISEASE, AND AGING USING YOYO TM
Astronauts may experience lower limb muscle loss amounting to 10% in the first month of spaceflight (LeBlanc et al., 1995;Tesch et al., 2005). In parallel, loss of bone mineral density amounts to ∼1% monthly during lack of weight bearing (Shackelford et al., 2004;Sibonga et al., 2007). Similar to the impact of the 0-g environment, injuries, diseases or other conditions leading to severely reduced levels of physical activity and skeletal muscle unloading, exert immediate, obvious negative effects on muscle size, function and integrity. It is worth noting that marked skeletal muscle protein breakdown and associated molecular changes are apparent after only 3 days of unilateral lower limb suspension (ULLS; an established spaceflight analog to study skeletal muscle). Muscle unloading  resulting from withdrawal of weight-bearing activities alters expression of pathways and markers for contractile protein breakdown and synthesis Gustafsson et al., 2010;Reich et al., 2010). Such compromised protein metabolism appears to facilitate significant muscle loss within 5 days (Wall et al., 2014). In clinical practice, this would imply that exercise countermeasures aimed at combatting negative consequences of muscle disuse should be implemented as early as medically possible. Thus, the efficacy of YoYo TM exercise training should be explored in patients and populations at obvious risk of suffering from muscle deconditioning.

Lower Limb Unloading and Bed Rest
Quadriceps muscle volume decreased by 9% in men and women subjected to 5 weeks of ULLS. In parallel, muscle strength decreased by ∼30%. In contrast, when concurrently employing YoYo TM resistance exercise twice or thrice weekly, offering only 16 min contractile activity over the course of this intervention, muscle volume rather showed an impressive 8% increase . Similarly, the marked strength loss noted after ULLS only was offset. At the molecular level, there were reductions in total RNA as well as in actin and myosin mRNA expression following ULLS. These changes were counteracted by YoYo TM knee extensor exercise (Haddad et al., 2005). Similarly, ULLS decreased PGC-1alpha, and increased phosphofructokinase expression (Fernandez-Gonzalo et al., 2014a). Despite the limited amount of work produced, these effects were offset by concurrent YoYo TM exercise. This suggests that skeletal muscle metabolic perturbations, and most notable the reduced oxidative capacity, could be attenuated by bouts of high-force, low-volume YoYo TM resistance exercise.
Furthermore, 29 and 90 days' bed rest decreased quadriceps muscle size by 10 and 18%, respectively. This marked atrophy was offset when YoYo TM exercise (supine squat; 4 sets × 7 reps) was carried out every third day (Alkner and Tesch, 2004a,b). Longterm bed rest also compromised motor control functions. Thus, the EMG amplitude required to produce a certain force task, or sustain an isometric action, showed noticeable increases (Alkner et al., 2016). These investigators also reported reduced rate of force development following bed rest. Most importantly however, all these effects were abolished in individuals who concurrently performed YoYo TM exercise. It is also worth noting that heel raises and supine squats performed every third day using YoYo TM was equally effective as an established pharmaceutical (Pamidronate) intervention against bone loss, to blunt the decrease in bone mineral density experienced after 90 days' bed rest (Rittweger et al., 2005). Further, while m. vastus lateralis collagen/muscle protein content ratio increased in response to bed rest, it remained unchanged in individuals who performed concurrent YoYo TM exercise (Nielsen et al., 2016). This exercise regimen also counteracted some, but not all, muscle metabolic perturbations induced by the 90 days' bed rest (Irimia et al., 2017).
Altogether, prescribing YoYo TM exercise, employing eccentric overload, appears highly effective in combating muscle atrophy and dysfunction and metabolic perturbations. The method may also attenuate loss or alterations of other tissues impacted by long-term disuse or lack of weight bearing. Short-term interventions (<3 weeks) employing resistance exercise using weights (not feasible in 0-g) as countermeasures also abolish strength and muscle loss (Schulze et al., 2002). There are no long-term bed rest studies available employing feasible resistance exercise methods for in-flight use that have explored in detail adaptations proving efficacy in counteracting neuromuscular dysfunction occurring during spaceflight.

Aging
Resistance exercise training is now an established method of treating age-induced skeletal muscle atrophy, i.e., sarcopenia. YoYo TM exercise appears to serve this cause more effectively than that noted with traditional weight training. Thus, in ∼70year old men and women, 12 weeks YoYo TM knee extensor training increased isokinetic power by 28%. This effect was significantly greater than noted in age-matched individuals who trained with weights (Onambele et al., 2008). Likewise, YoYo TM but not weight-stack exercise, improved single-leg balance. The authors attributed this response to increased tendon stiffness and neuromuscular transfer/overspill to the plantar-flexors in those who trained with YoYo TM . This exercise task also called for significantly higher overall EMG activity. Further, increases in muscle volume (5%) and isometric and isotonic force (∼10%) were noted following 8 weeks YoYo TM Leg Press exercise combined with high-intensity aerobic training in 70-year-old healthy men (Bruseghini et al., 2015). While this study did not investigate conventional weight training, reports comparing eccentric and conventional resistance training in older adult show no differential effect on muscle size and strength across exercise modes.
As resistance exercise remains the most established, yet underutilized, method to treat age-induced skeletal muscle loss, we urge the use of YoYo TM exercise in future investigations aimed at exploring adaptations of resistance exercise in the physically fit, but also in the impaired and dysfunctional elderly. Amid caution must be exercised when subjecting frail or impaired populations to this method there is strong support these individuals benefit more from high-than low-intensity exercise (Peterson et al., 2010).

INJURY PREVENTION AND REHABILITATION
The efficacy of YoYo TM exercise to prevent hamstring injury was examined in 30 soccer players of the Swedish premiere league (Askling et al., 2003). While half of the players, in addition to their prescribed pre-season training routines, performed hamstring exercise for 10 weeks using the YoYo TM Leg Curl, the other players did not. Over the course of the competitive season, hamstring strain injury occurrence was significantly lower in the training group (3/15) than in players who did not receive this treatment (10/15). In support, de Hoyo and collaborators noted that there was a likely reduction in the number of days of absence per injury, and a possible drop in total injury incidence in young soccer players subjected to concurrent YoYo TM Squat and Leg Curl training (de Hoyo et al., 2015). Thus, it appears the improved vertical and linear speed or power demonstrated with this program (see above) was accompanied by reduced hamstring injury incidence and severity. Although, it remains to be established whether these effects are more substantial than those realized with other forms of accentuated eccentric loading paradigms, these findings suggest that YoYo TM exercise not only benefits athletic performance but could also serve as an important adjunct to combat hamstring muscle strain, and perhaps other soft-tissue injuries.
The effects of open chain knee extensor exercise, using either YoYo TM or a weight-stack machine were compared in individuals with a history of knee ligament injury (Greenwood et al., 2007). The YoYo TM paradigm was equally, if not more effective as the more conservative approach to improve muscle strength and size, neural activation, standing balance, and vertical jump performance. Similarly, athletes with chronic patellar tendinopathy who completed a 6-week training program employing the closed chain YoYo TM Leg Press, showed an impressive (90%) increase in eccentric strength. More significantly, clinical measures showed reduced pain and augmented tendon function. The results of this study suggest that short-term training using inertial eccentric overload has significant and beneficial effects on muscle function and pain in individuals suffering from long-lasting patellar tendinopathy (Romero-Rodriguez et al., 2011).
Athletes such as volley-and basketball players are at high risk of developing patellar tendinopathy. Given the paradox that eccentric training elicits performance and therapeutic benefits, yet might provoke such injury, prescribing exercise to these athletes is a delicate balancing act. Hence, in a subpopulation of 81 male and female players who carried on their normal in-season training routines over 24 weeks, a single bout YoYo TM Squat was prescribed once weekly (Gual et al., 2016). Neither group suffered from increased symptoms of patellar tendinopathy. Yet, increases in vertical jump, strength and power were most evident in those athletes receiving the high-intensity bout. It appears, therefore, that adding a weekly YoYo TM Squat bout to the prescribed regular routine enhances lower limb muscle power, without causing patellar tendon complaints. Similarly, 41 recreational or competitive athletes suffering from patellar tendinopathy were prescribed YoYo TM Leg Press exercise while treated with intra-tissue percutaneous electrolysis. According to the authors, only a few sessions of this combined paradigm allowed patients to return to previous physical activity levels as they experienced markedly improved knee function (Abat et al., 2014). Further, calf raise exercise training performed using the YoYo TM Squat, increased Achilles tendon cross-sectional area as well as the pennation angle of the medial aspect of the gastrocnemius muscle (Sanz-Lopez et al., 2016). Albeit there were no clinical outcome measures reported, these results suggest that eccentric overload training with YoYo TM Squat promotes muscle and tendon adaptations that could benefit athletic performance and serve to prevent injury. This accords with a wealth of clinical studies demonstrating the efficacy of eccentric exercise training as an aid in treating tendon disorders (O'Neill et al., 2015).

PHYSIOLOGICAL EFFECTS OF CONCURRENT ISO-INERTIAL AEROBIC AND YOYO TM RESISTANCE EXERCISE
While resistance exercise effectively combats muscle atrophy and dysfunction, it does not prevent cardiovascular deconditioning. Astronauts suffer from both skeletal muscle and cardiovascular deconditioning while in orbit. Yet, future space vehicles on missions to distant planets will only carry a single exercise apparatus with the objective of preserving both muscle and cardiovascular function. To meet this challenge, our laboratory recently introduced a YoYo TM configuration (RAD; Resistance and Aerobic exercise Device) accomplishing concentric rowing exercise as an additional, sole aerobic feature . In a proof-of-principle study (Owerkowicz et al., 2016), seventeen men and women completed 5 weeks of training employing the YoYo TM RAD. Supine Squats (4 sets of 7 reps) were performed twice weekly, and aerobic rowing (4 × 4-min) at ∼90% VO 2max three times weekly. VO 2max (8%), 3-RM strength (18%), and quadriceps femoris cross-sectional area (10%), as well as fatigue resistance of the knee extensor muscles increased significantly. At the cellular and molecular level, muscle fiber size, citrate synthase activity, total RNA concentration, IGF-I mRNA, and Type IIa MHC mRNA showed marked increases. These functional outcomes and biomarker changes imply that low-volume concurrent YoYo TM aerobic and resistance exercise results in cardiovascular and musculoskeletal benefits comparable to those noted with more established exercise modalities. Subsequently, this research team investigated 19 men and women who were subjected to 10 days simulated spaceflight (ULLS). Ten of these individuals performed additional exercise using this particular YoYo TM RAD paradigm. While ULLS had profound adverse effects on skeletal muscle molecular markers and in-vivo function, the exercise intervention mitigated these changes, and was in fact capable of ameliorating both muscle strength and VO 2max (Cotter et al., 2015).
These findings are in stark contrast to research carried out almost 40 years ago, raising questions about the compatibility of aerobic and resistance exercise (Hickson, 1980;Leveritt et al., 1999). Albeit the seminal work by Hickson deserves recognition, unfortunately the conclusions drawn from this single study have become dogma. Indeed, employing more accurate protocols and currently available imaging and molecular methods, and combining smart and thoughtfully, concurrent aerobic and resistance exercise training could in fact amplify certain established exercise responses in non-athletic populations (Lundberg et al., 2013;Murach and Bagley, 2016). In further support, the very robust strength increase in 70-year old men, noted in response to YoYo TM Leg Press training, did not attenuate favorable changes in aerobic fitness, body composition, or blood lipid (LDL cholesterol) profile, elicited by a preceding aerobic exercise intervention (Bruseghini et al., 2015). Thus, YoYo TM training appears not to interfere with the beneficial effects of aerobic training in healthy senior men. This accords our demonstrations of important skeletal muscle adaptations following iso-inertial endurance exercise combined with YoYo TM resistance exercise training in healthy, young men (Lundberg et al., 2013(Lundberg et al., , 2014. Hence, concurrent aerobic and resistance exercise may boost skeletal muscle hypertrophy (Mikkola et al., 2012;Lundberg et al., 2013), and may, in fact, produce positive effects on lean body mass and cardiovascular health markers similar or more profound than those evoked by aerobic or resistance exercise alone (Sillanpaa et al., 2010;Johannsen et al., 2016). In view of this, we are inclined to state that sedentary or recreationally active individuals can enjoy the benefits of YoYo TM exercise programs combining strength, power and endurance exercise of postural weight bearing muscles without compromising the effects of either mode when executed alone. It remains to be investigated if concurrent aerobic and resistance exercise protocols, employing other exercise modalities, elicit responses on par with the above findings.

NEUROLOGICAL REHABILITATION
Evidently, eccentric actions per se play a predominant role in producing increases in muscle strength, power, and size (Dudley et al., 1991b;Hather et al., 1991;Hortobagyi et al., 1996). This may be because eccentric actions rely on unique neural strategies to facilitate and evoke motor action potentials and bring motor units into play (Enoka, 1996;Hedayatpour and Falla, 2015). Further, with use of brain functional MRI, it has been shown that eccentric actions engage more functional regions of the brain than their concentric counterparts (Fang et al., 2004). Thus, eccentric actions are important in both central and peripheral nervous system adaptations in response to resistance exercise training. The first study assessing the feasibility of YoYo TM Leg Press exercise as a rehabilitation intervention for neurologically-impaired stroke patients, reported robust gains in muscle power and force after 8 weeks of training, accompanied by significant improvements in balance and gait (Fernandez-Gonzalo et al., 2014c). Spurred by these findings, Fernandez-Gonzalo and associates designed and conducted a more comprehensive randomized clinical trial assessing cognitive performance along with changes in quadriceps muscle volume, force, power, and daily life functions in chronic stroke patients subjected to 12 weeks YoYo TM Leg Press training (Fernandez-Gonzalo et al., 2016a). The results of this trial confirm and highlight the efficacy of this particular exercise paradigm to aid stroke patients regaining muscle mass, strength, and critical daily physical functions. However, while 12-week resistance exercise programs using concentric and eccentric actions by means of weights may produce similar results in stroke patients (Ryan et al., 2011), they would require at least six times the number of repetitions to be performed. Most remarkable, the exercise intervention (28 reps twice weekly), which called for less than 4 min of contractile activity per week (Fernandez-Gonzalo et al., 2016a), also improved vital cognitive functions such as executive performance, attention, and speed of information processing, suggesting YoYo TM exercise evoked paramount central nervous system adaptations. Such a response would be commensurate with the demonstration of muscle action-specific involvement of certain areas of cortex (Fang et al., 2001;Hedayatpour and Falla, 2015). Those findings are encouraging and should be followed by studies using, e.g., brain fMRI to discern the specific mechanisms and areas of cortex targeted with this unique exercise stimulus. Clinical trials in individuals suffering from other neurological pathologies are warranted to justify YoYo TM exercise as a viable and safe rehabilitation method.

GUIDELINES FOR YOYO TM EXERCISE TRAINING
The standard YoYo TM exercise protocol (4 sets of seven repetitions; 90-180 s rest between sets) should be performed no more than twice weekly with at least 48 h recovery between sessions. More frail individuals or populations suffering from disorders should be allowed the full 180 s rest between sets. In patients undergoing rehabilitation from injury or trauma and concurrently subjected to other exercise regimen(s), YoYo TM exercise performed once weekly is advised. In healthy individuals subjected to endurance and resistance exercise training of the same muscle group on the same day, any all-out aerobic exercise session should be performed at least 6 h prior to YoYo TM exercise. In more frail populations, caution and careful tracking and monitoring of performance (e.g., power), in each session and over time, is necessary to ensure full recovery and uncompromised performance. If training for power is preferred, lower inertia should be chosen. Should training rather target force development, high inertia should be chosen. Training progress should occur by encouraging the trainee to delay the breaking eccentric action, which results in increased eccentric overload. High training volume or frequency is not a necessity. As there is limited knowledge about responses to YoYo TM exercise using upper-body muscles, the above guidelines apply to exercise involving weight-bearing and lower-limb muscles.

SIDE EFFECTS AND SAFETY ISSUES
Feasibility and safety issues employing various YoYo TM configurations, e.g., open-or closed chain knee extensions, leg curl, vertical or supine squat, calf raise, back extension, arm curl or row, have been reported in studies of professional athletes, recreationally active, sedentary or disabled individuals of either sex and ranging in age from young adults to +90-year-old men. Collectively, in these individuals, being ambulatory or subjected to muscle unloading, long-duration (up to 110 day) confinement or bed rest, or returning from space, no serious muscle-tendon injury or severe muscle soreness (delayed onset of muscle soreness; DOMS) or complaint has been reported during or following YoYo TM use.
It is generally held that novel eccentric exercise provokes muscle damage and subsequent inflammatory symptoms, resulting in DOMS (Newham et al., 1983;Hortobagyi et al., 1998;Krentz and Farthing, 2010;Fernandez-Gonzalo et al., 2012). Thus, established skeletal muscle "damage markers" were assessed in 32 men and women at onset of, and following the very last training session of a 6-week program comprising 2-3 weekly bouts using the YoYo TM supine squat (Fernandez-Gonzalo et al., 2014b). While creatine kinase and lactate dehydrogenase levels were elevated after novel YoYo TM exercise, this response was not evident after the very last bout. Still, muscle power was ∼50% greater than noted initially (Fernandez-Gonzalo et al., 2014b). Taken together, muscle damage is not likely to interfere with desired exercise-induced muscle adaptations evoked by YoYo TM exercise training due to the protective effect from repeated training bouts. Nonetheless, supervised, familiarization (≥3 sessions) using progressively increased effort, and hence load, is recommended to ensure good form, comfort, and consistent performance to reduce DOMS or injury risk. Individuals employing this strategy typically showed steady progression in force and power across sessions in the course of short- (Lundberg et al., 2013) or long-term (Alkner et al., 2003) training programs, with maintained or increased self-reported comfort. Notwithstanding, when introduced to novice or clinically frail individuals, caution should be exercised to allow for complete recovery between sessions and ensure effort is progressive. Thus, excess eccentric exercise may be counterproductive or even injurious to certain populations and may not be prescribed unconditionally to patients suffering from muscle-or neurological disorders. However, people recovering from stroke coped well with the maximal nature of YoYo TM exercise. In fact, patients showed 100% adherence to the protocol referred to above and improved peak power at a weekly rate of ∼5% without experiencing DOMS or increased muscle spasticity (Fernandez-Gonzalo et al., 2014c, 2016a. The safety, feasibility and efficacy of YoYo TM to serve in neurological rehabilitation are further evident in patients suffering from multiple sclerosis and Alzheimer's disease. Hence, after complying with a 12week intervention comprising YoYo TM Squat exercise (Sarmiento et al., 2014;Oliveira et al., 2015) these individuals demonstrated markedly improved gait performance and muscle strength with no severe medical complications.

SUMMARY AND FUTURE PERSPECTIVES
Chronic exercise training using YoYo TM produces early, robust neuromuscular adaptations, which appear to be more pronounced than noted with traditional weight training. Improvements in strength and power stem from preeminent skeletal muscle hypertrophy and increased neuronal activity, inferring the unique iso-inertial loading strategy typical of YoYo TM exercise offers a highly potent stimulus to optimize the benefits of resistance exercise. The method is in the advent of clinical use. Although there is strong support that this exercise paradigm could improve function in patients suffering from, e.g., neurological pathologies, age-induced sarcopenia or musculo-tendinous problems, there is call for fine-tuning and exploring individualized protocols to be prescribed for men and women with clinical symptoms. Validating and revising currently employed protocols and prescriptions with regard to, e.g., exercise frequency, volume and/or inertia for individual and disease-specific use, would assure larger populations could safely entertain the benefits of YoYo TM exercise training. Due to the time constrains of current institutional health care and rehabilitation systems, there is a need to define the minimum dose required to induce the desired beneficial effects prompted by this exercise paradigm. Thus, studies of different clinical populations, comparing the efficacy of YoYo TM and other exercise methods, are warranted to define protocols optimizing exercise benefits and ensure patients are not "under-loaded" or at risk of being "over-loaded." The demonstration of important neuropsychological benefits induced by YoYo TM exercise in stroke patients deserves attention. We urge investigators to conduct research addressing the underlying mechanisms incurring such adaptations. Likewise, as therapeutic aids to improve cognitive functions are routinely used in rehabilitation following brain trauma, the potential benefits or drawbacks of employing YoYo TM exercise in a virtual reality environment should be explored. Based on our studies encompassing stroke victims, we believe protocols offering simultaneous neural-, muscle-and cognitive activation, could present a contingent challenge and valuable asset in neurological rehabilitation (Figure 2).
YoYo TM exercise protocols should be tested in other not explored, clinical conditions characterized by muscle loss and impaired neuromuscular function, and/or dysfunctional endocrine or metabolic control. Examples of such conditions, which interfere with daily living physical abilities, include, e.g., cancer, cachexia, burns, kidney failure, heart failure, muscle dystrophies, chronic alcoholism, and various autoimmune diseases. Further research in various patient categories, exploring physiological adaptations to YoYo TM exercise in comparison with other forms of resistance training, could aid in generating new effective exercise therapies to combat dysfunction while improving quality of life. Until then, extrapolating results from currently available studies of healthy men and women subjected to YoYo TM exercise, to non-explored clinical conditions should be done with caution. Notwithstanding, with the current information at hand it appears YoYo TM exercise serves as a useful tool for improving neuromuscular function in both healthy and clinical populations.

AUTHOR CONTRIBUTIONS
Conception and design of the work: PT, RF, and TL. Drafting the work and revising it critically for important intellectual content: PT, RF, and TL. Final approval of the version to be published: PT, RF, and TL. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: PT, RF, and TL.

FUNDING
Research employing YoYo TM conducted by PT and referred to herein, have been funded by grants from the National Astronautics and Space Administration (NASA), the National Space Biomedical Research Institute (NSBRI, the European Space Agency (ESA), the Swedish National Space Board (SNSB) and the Swedish Research Council for Sport Science (CIF).