Reprogramming metabolic gene expression during active recovery following disuse

The importance of studying recovery strategies following atrophy

Periods of muscle unloading and reduced neural activity often occur following injury and hospitalisation. This induces significant declines in strength and muscle size (i.e. atrophy), downstream of increases in inflammatory cytokines, mitochondrial dysfunction, anabolic resistance, and disruption of proteostasis. This shifts the balance between protein synthesis and degradation, resulting in a net loss of skeletal muscle proteins, resulting in fibre atrophy and loss of force production. Alongside fibre atrophy, factors affecting specific force, such as the arrangement and quality of sarcomeres, motor unit recruitment, and metabolic capacity can contribute to overall detriments in strength seen with disuse.

While exercise prehabilitation prior to disuse has gained attention in the context of preventing muscle loss during elective periods of hospitalisation, surgery, bed rest, or disuse (Smeuninx et al., 2021, 2025), we still lack strategies for effectively treating disuse atrophy in older individuals that often present delayed or incomplete recovery compared to their younger counterparts.

In this issue of The Journal of Physiology, Franchi et al. examine resistance training during recovery which has scarcely been investigated at the molecular level (Franchi et al., 2025; Sarto et al., 2022). Eleven young healthy and recreationally active male volunteers had measurements taken for muscle morphology via ultrasonography, isometric maximum voluntary contraction via muscle dynamometry and vastus lateralis biopsies for immunofluorescent, morphological and biochemical analysis at baseline (LS0), following 10 days of unilateral lower limb suspension (LS10) and following 21 days of active recovery (AR21). Active recovery consisted of 9 resistance training sessions (3/week), each consisting of three sets of 10 repetitions of unliteral leg press and leg extension exercises at 70% of one-repetition maximum.

Transcriptional signatures of active recovery post-disuse

As expected with 10 days of unilateral limb suspension, maximum voluntary contraction was reduced by ~30% but restored to pre-suspension levels after active recovery. Very modest changes in muscle loss were observed with disuse (~3%–4%), but intriguingly, the active recovery regime both restored and also increased vastus lateralis volume by ~20% compared with baseline measurements suggesting the active recovery was highly effective at inducing growth beyond the starting state.

Histologically, the number of slow expressing myofibres increased after active recovery, accompanied by a decrease in the number of ‘Fast’ expressing myosin fibres compared with baseline. Perhaps most intriguingly, Franchi et al. report a number of molecular features classically associated with endurance-like exercise training when comparing muscle post-active recovery to baseline. For example, while SDH activity was unaffected by disuse, on average, participants had an 18.7% increase in SDH activity compared with baseline following active recovery. Furthermore, glycogen content as measured through PAS staining increased by ~15% compared to baseline and post-limb suspension.

Transcriptome analysis of muscle following disuse demonstrated a downregulation of genes enriched in hallmarks/pathways relating to ‘oxidative phosphorylation,’ ‘fatty acid metabolism,’ ‘mitochondrial biogenesis,’ and ‘TCA-Cyle’ related terms. Interestingly, following active recovery these terms/hallmarks were enhanced beyond baseline levels suggesting a remarkable reprogramming of oxidative metabolism in an effort to support recovery of muscle. Perhaps the largest caveat of this study is the absence of a control group that underwent recovery through normal ambulation, to ascertain whether this glycogen response was a supercompensation to a robust exercise regimen, or a feature of normal re-ambulation post-disuse. Exisiting meta-analyses (MetaMEx) of resistance exercise transcriptional responses suggest this was a unique feature of this study However, how long this elevated glycogen content remains or can be enhanced remains interesting conceptually.

These results complement a recent study by Shur et al., who subjected 10 healthy males to 3 days of bedrest followed by 3 days of ‘exercise-supplemented remobilisation’ (Shur et al., 2024). In this study, a similar volume of leg muscle mass was lost, with reductions in myofibrillar protein synthesis and breakdown, as well as reductions in insulin-stimulated leg glucose uptake and glycogen storage (similar to levels observed with severe insulin resistance and metabolic syndromes). Interestingly, 3 days of exercise-supplemented remobilisation failed to restore these metabolic parameters, but did restore myofibrillar protein synthesis, which was not observed by ambulation alone. Gene expression analysis comparing muscle at baseline vs. post-exercise-supplemented remobilisation displayed an upregulation of 29 genes, including transcription factors, coactivators and nuclear receptors (PPARGC1A, HIF1A, FOXO1, PPARA) and genes encoding key glycolytic/TCA cycle enzymes, glucose handling components and genes involved in glycogen synthesis/breakdown (GAPDH, CS, PFKM, SLC2A4, HK2, PDK4, PYGM, GYS1).

While these gene signatures complement the findings of Franchi et al. (2025), this upregulation was observed despite no evidence of increases in muscle glycogen storage, as also reported by Franchi et al. (2025). These two independent studies highlight the importance of multiple sampling points to understand the temporal transcriptional changes that precede proteomic remodelling and resultant changes in physiological function/recovery and metabolic health.

Why is metabolic gene regulation important for protein biosynthesis in muscle?

To date, the majority of disuse and recovery studies have focused on tilting the balance of proteostasis, to create a net gain of muscle proteins and resultant restoration/hypertrophy of skeletal muscle. Less attention has been given to the metabolic requirements of remodelling the proteome post-disuse and in the recovery of muscle protein (Baumert et al., 2024). Protein synthesis has an estimated metabolic cost of ~5 ATP molecules per peptide bond formed, which is used to activate amino acids and charge tRNAs to form polypeptide chains (Princiotta et al., 2003).

Skeletal muscle is made up of extremely large contractile proteins such as myosin heavy chains, consisting of 2–3000 peptides, as well as the largest protein found in vertebrates, titin, consisting of ~34,350 peptides. To use the latter as an example, broadly speaking, to synthesize one molecule of titin, ~171,745 ATP molecules would be required, requiring ~4770 glucose molecules through oxidative phosphorylation if completely efficient. In T-cells, it has been demonstrated that inhibition of both glycolysis and oxidative phosphorylation results in a strong decrease in protein synthesis (Princiotta et al., 2003).

The observed increases in glycogen content, SDH activity, and the reprogramming of oxidative and carbon metabolism gene pathways following active recovery (as demonstrated in complementary studies: (Franchi et al., 2025; Shur et al., 2024)) may enhance both metabolic capacity and flexibility. These adaptations probably support the elevated energy demands associated with achieving a net positive proteostasis balance, either preceding or occurring simultaneously with hypertrophy. This hypothesis aligns with findings from animal hypertrophy models in which pro-growth pathways can be observed acutely following resistance exercise but do not lead to hypertrophy because of energy availability (Viggars et al., 2023).

Future directions

The findings from these studies underline the need for optimised rehabilitation strategies tailored to individuals recovering from periods of disuse. Beyond restoring muscle mass and force production, the remarkable reprogramming of oxidative metabolism and glycogen supercompensation suggest that exercise regimens can enhance metabolic flexibility and energy availability – critical factors for sustained muscle recovery. This holds particular significance for older populations, who often experience delayed or incomplete recovery due to anabolic resistance and impaired metabolic responses. Developing targeted interventions that integrate resistance training with metabolic support could therefore address both the physiological and metabolic demands of recovery. Future research should focus on comparing different exercise modalities, exploring long-term sustainability of metabolic adaptations, and identifying molecular markers that predict recovery outcomes. Furthermore, there is also a necessity for future studies to include or exclusively study female subjects. These efforts will provide valuable insights for clinical and rehabilitation settings, ultimately improving recovery trajectories for diverse patient populations.

Supplementary Material

Supporting information

Additional supporting information can be found online in the Supporting Information section at the end of the HTML view of the article. Supporting information files available: