Your Muscles Remember Your Strongest Moments—And Your Weakest
Before Adam Sharples became a molecular physiologist studying muscle memory, he played professional rugby. Over his years as an athlete, he noticed that he and his teammates seemed to return to form after the offseason, or even from an injury, faster than expected. Rebuilding muscle mass and strength came easy: It was as if their muscles remembered what to do.
In 2018, Sharples and his research lab, now at the Norwegian School of Sport Sciences in Oslo, were the first to show that exercise could change how our muscle-building genes work over the long term. The genes themselves don’t change, but repeated periods of exertion turns certain genes on, spurring cells to build muscle mass more quickly than before. These epigenetic changes have a lasting effect: Your muscles remember these periods of strength and respond favorably in the future.
Intuitively, this makes sense. Past exercise primes your muscles to respond more robustly to more exercise. Over the past few years, Sharples’s lab has found that muscles have additional molecular mechanisms for remembering exercise; he and other scientists have been building on this research, too, confirming epigenetic muscle memory in young and aged human muscle, after different modes of training, as well as in mice. Now 40 years old, Sharples is still thinking about how our muscles remember but has lately been investigating the inverse trajectory: Do muscles have a similar memory for weakness?
The answer appears to be yes. “Our new data shows that muscle does not just remember growth—it also remembers wasting,” Sharples told me, of a study published in preprint on bioRxiv and currently in peer review for Advanced Science. “The more encounters you have with injury and illness, the more susceptible your muscle is to further atrophy. And, well—that’s what aging is, isn’t it?”
The Norwegian government’s research council has been funding Sharples’s research and has a vested interest in the lab’s discoveries. In the next decade, Norway is expected to become a “super-aged society,” in which more than one in five people are age 65 or older. Japan and Germany have already crossed this threshold, and the United States is expected to reach it by 2030. Age-related muscle weakness is a major factor in falling risk; falling is a leading cause worldwide of injury and death in people 65 and older. Better understanding how muscles remember and react to their weakest moments is a crucial step toward knowing what to do about it.
As part of the new study, Sharples’s team studied repeated periods of atrophy in young human muscle, using a knee brace and crutches to immobilize participants’ legs for two weeks at a time. This level of disuse, Sharples said, is comparable to real-world situations in which muscle rapidly loses size and function—limb immobilization after fractures or other injuries, periods of hospitalization or bed rest, reduced weight-bearing during recovery. A couple of years ago, I went to observe this research for my book On Muscle; one study participant, an avid skier and cyclist, told me he was shocked by how significantly the muscles in his leg deteriorated after just a couple of weeks of immobilization. The team also ran a concurrent study in aged rat muscle, in collaboration with Liverpool John Moores University; in both studies, repeated periods of disuse led to epigenetic changes—shifts in the way genes were expressed.
These changes affected the core functions of muscle cells, hampering the genes in mitochondria—the powerhouses of the cell, which generate the energy required to contract and relax muscle fibers. Letting muscles weaken suppressed genes involved in mitochondrial function and energy production in particular, including genes that are essential for muscle endurance and recovery. The researchers also found that a key marker of mitochondrial abundance dropped more drastically after repeated atrophy than after the first episode, indicating that repeated disuse makes muscle more vulnerable. In other words, the evidence suggests that every time you fall down the hole, it becomes more difficult to climb back out.
Similar changes occurred in both the young human muscle and the aged rat muscle. But the young muscle could adapt and recover. After repeated atrophy, it showed a less exaggerated gene-expression response than the aged muscle did. “There seems to be some resilience and protection with young muscle the second time around,” Sharples said. He likened this to an immune-system response: Young muscle responds better to atrophy the second time because it has encountered it before and knows how to bounce back. By contrast, aged muscle becomes more sensitive after repeated atrophy, showing a worsened response with the second episode.
How long our muscles hold on to any of these memories is still up for debate. “Because of our study periods, we do know with some certainty that epigenetic memories can last at least three to four months, and that protein changes can also be retained,” Sharples said. “How long after that is difficult to say. But we know from our studies of cancer patients that epigenetic changes in muscle were retained even 10 years out from cancer survival.”
This was startling to hear. If an adverse health event is dramatic enough, like cancer, our muscles can carry the effects of that for a decade or more. More typically, though, inactivity, aging, and repeated episodes of disuse may gradually shift the system toward a state in which weakness becomes more entrenched and recovery slower.
Understanding what drives muscle to remember being in stress situations—either beneficial, like exercise, or damaging, like illness—could help us better judge what to do about this, says Kevin Murach, an associate professor at the University of Arkansas who studies aging and skeletal muscle and who was not involved in the new study. Knowing the mechanisms that drive beneficial changes at the molecular level could help develop drugs with similar effects. On the other end of the spectrum, if illness and immobilization have long-term negative effects, Murach told me, the next question to answer is: “Can we use exercise to offset that?”
Both Murach and Sharples said the data are getting only more robust that strength training, paired with endurance or high-intensity interval training, is the best therapy to protect against age-related loss of muscle and function. “Perhaps the key takeaway is that at any point along this continuum, new exercise or loading stimuli can still shift the balance back towards growth and health,” Sharples said. “I don’t think there is a point at which muscle can’t respond at all—it simply becomes less efficient when repeatedly weakened or when older.”
Identifying genes associated with muscle growth, as well as pharmaceutical targets, could mean that drugs or gene therapy may eventually be able to assist with boosting muscle response for people who cannot exercise. Murach and Sharples cautioned, though, that stimulating muscle-cell growth can have unintended consequences, in part because growth pathways are common across cell types—including cancer cells.
What the new work does show is that our muscle mass is not a blank slate. “What we’re finding suggests that our muscles may carry a history of both strength and weakness,” Sharples said. It’s shaped by factors including age, baseline muscle health, previous atrophy events, and previous exercise training. “And that history shapes how our muscles respond in the future.” I came away from our conversation thinking about the battle between positive muscle memory for strength and negative muscle memory for atrophy as a kind of tug-of-war: The two are constantly in tension, but the more experiences you have of one or the other, the more it pulls you into its embrace.