Unraveling the Mysteries Behind Enhanced Physical Performance

If you’ve ever played basketball, whether professionally or recreationally, you’ve likely wondered what it would be like to dunk the ball. With a running start, you can envision yourself hanging from the rim with a rush of adrenaline and sheer weightlessness. If you’ve ever tried, you know just how difficult this comes to most of us, and yet there are people to whom this comes naturally. According to unofficial records, Michael Jordan holds the title for the highest vertical jump in NBA history at a whopping 48 inches tall – a total of 16 Kraft Singles high! Of course, height plays a major role in this unique ability, but there are likely other mechanisms in place that predispose certain athletes to have “bounce”. Based on recent athletic performance research, the secret lies within the musculoskeletal system which consists of an intricate network of muscles, bones, tendons, and ligaments.

The musculoskeletal system plays an important role in the movement and coordination of the body and requires fine-tuning of our muscular circuitry. This circuit involves timely muscle contraction and flexion as well as connections to neighboring joints, tendons, and ligaments. Perturbations within this circuit can lead to diseases such as arthritis, fibromyalgia, and a variety of pain conditions. In fact, musculoskeletal conditions remain the highest contributors to the rehabilitation industry and affect nearly 1.7 billion people worldwide (Cieza et al. 2021). On the other end of the spectrum, physical exercise and genetics can have anabolic effects, such that they help build body tissue and improve the overall function of muscles and tendons. However, for many years, it was unclear what major factors were at play to result in enhanced physical fitness.

In a recent study, Ryo Nakamichi and colleagues looked into the role of a protein, Piezo1, in enhanced physical performance (Nakamichi et al. 2022). Piezo1 is a mechanosensitive ion channel, meaning the channel opens when physical pressure is placed on the cell membrane. The authors focus on a particular gain-of-function mutation of Piezo1 in humans – E756del. For the purpose of this study, they utilize a similar murine mutation, R2482H. Due to Piezo1 being expressed in a variety of tissues and organs, this group uses several genetic models: a systemic-wide knock-in that introduces the mutation in all Piezo1 channels in the body, a tendon-specific knock-in, and a muscle-specific knock-in. To study the distinct phenotypes of these mutations, both mice with mutations and wild-type mice without mutations, are subjected to a long-jump assay and a run-to-exhaustion test. In the long jump, both the systemic knock-in mice and tendon-specific knock-in mice show enhanced physical performance by jumping approximately 1.5x the distance of wild-type mice. Although these two groups do not seem to run a greater distance than wild-type mice, their maximum speed is significantly greater, suggesting that this mutation in the tendon contributes to the higher exercise capacity.

Figure 1. Representative images of both wild-type and mutant mice performing in the long jump test. This Piezo1 tendon-specific mutation, R2482H, enhances the jumping ability of mice. Image from Nakamichi et al. 2022

To better understand the mechanisms by which this occurs, the authors take a closer look at the major tendon of the hind leg – the Achilles. This tendon connects the calf muscle to the heel and is used for walking, running, and jumping. In the systemic mutants and tendon-specific mutants, the Achilles' tendons were significantly wider with larger collagen fibrils, suggesting the mutation enhances tissue formation and enlargement. Upon closer inspection using RNA-sequencing analysis, they find that these two mutant groups have significant upregulation of tendon-related genes such as Mohawk and Schleraxis. Specifically, there was an upregulation of both collagen matrix- and non-collagen matrix-associated genes in the tendons which likely contribute to the structural changes observed in the Achilles tendon. Interestingly, there were no observable effects on the muscle among the four genotypes.

Finally, by taking a more biomechanical approach, the authors break down the jumping motion of these mice by analyzing the central position of the body, or centroid, during jump preparation, propulsion, and takeoff. From there, they could measure the angle of incidence and potential energy changes among the groups when jumping. Results from these experiments showed that the tendon-specific mutants generated more energy while jumping by bending the ankle joint more deeply with increased ankle flexion. This increased compliance of the tendon resulted in more stored energy, ultimately allowing these mice to jump farther.

One of the most interesting findings from this paper is that the enhanced physical performance that results from the R2482H mutation can be induced in mature animals following completion of major developmental milestones. Not only did these mice have an instantaneous improvement in physical ability but they also developed a wider Achilles and an upregulation of the same tendon-related genes. This finding has important clinical implications as it suggests that modulation of Piezo1 in tendons may function as a therapeutic target to treat musculoskeletal disorders in adults.

Scouring genetic databases, this group found that the human mutation, E756del, is prevalent in populations of African descent at around 18%. Taking a closer look at athletes of West African descent, they zero in on Jamaican sprinters who have competed in international sprinting, jumping, or throwing events. Of the 91 athletes, 46% were heterozygous for E756del while 8% were homozygous. Of the 108 controls, only 31% and 2% were heterozygous and homozygous, respectively. These data, however, are preliminary and only suggest a trend of enhanced athletic ability in this subpopulation. Despite being an interesting statistic, a larger cohort is necessary to make any significant conclusions. Although not a lot can be said yet about this specific human mutation, the role of tendon-specific Piezo1 in the physical ability of mice is a major step toward understanding the intricacies of musculoskeletal function and what it means to have a “natural” gift.

Edited by Lindsey Mehl.

REFERENCES

Cieza, A., et al. "Global estimates of the need for rehabilitation based on the Global Burden of Disease study 2019: a systematic analysis for the Global Burden of Disease Study 2019." The Lancet, vol. 396, no. 10267, 2021, pp. 2006-2017.

Nakamichi, Ryo, et al. "The Mechanosensitive Ion Channel PIEZO1 Is Expressed in Tendons and Regulates Physical Performance." Science Translational Medicine, vol. 14, no. 647, 2022, eabj5557.