Muscles retain molecular memory of repeated inactivity

Muscle loss, or atrophy, due to inactivity is common after illness, injury, hospitalization or falls, and becomes increasingly frequent with aging. New research published in Advanced Science shows that skeletal muscle retains a "molecular memory" of repeated disuse-and that this memory differs markedly between young and old muscles.

For the study, researchers combined repeated lower‑limb immobilization in young adults with an aged‑rat model to enable age comparisons. In young adults, repeated disuse resulted in a similar amount of muscle atrophy during both periods; however, the molecular response showed a protective memory. Oxidative and mitochondrial gene pathways were less disrupted the second time, indicating resilience.

In contrast, aged muscle developed a detrimental memory of disuse. Repeated inactivity caused greater atrophy, exaggerated suppression of aerobic‑metabolism and mitochondrial genes, activation of DNA‑damage pathways, among other effects. Across species, repeated disuse produced conserved alterations in metabolic gene networks, demonstrating that muscles retain long‑lasting molecular traces of atrophy.

Together, these findings show that repeated muscle disuse imprints a molecular memory that helps young muscle recover but makes aged muscle increasingly susceptible to further wasting.

Muscle carries a history of both strength and weakness, and these molecular memories may accumulate over time to shape how it responds when inactivity occurs again. Understanding how muscle records these past experiences of use and disuse is essential for designing better strategies to support recovery after illness, injury, or age‑related decline. This knowledge will help us determine not only when we should retrain, but also which type and intensity of exercise may be most effective. Our laboratory is now working with the Novo Nordisk Foundation to determine which exercise modes best evoke beneficial memory signals in the muscle's energy‑producing mitochondria, particularly in ageing muscle."

Adam P. Sharples, PhD, co‑corresponding author, professor at the Norwegian School of Sport Sciences, Olso