Aging leads to a decline in organismal homeostasis, increasing the risk of chronic diseases. Sarcopenia, the age-related loss of muscle mass and strength, contributes to physical frailty. This decline is linked to changes in skeletal muscle structure and metabolism, including defects in mitochondrial biogenesis, bioenergetics, and dynamics, as well as reduced protein synthesis and insulin resistance. Exercise is a promising intervention to mitigate these age-related changes, stimulating muscle protein synthesis and improving mitochondrial function. Different training intensities utilize different fuel sources; high-intensity exercise relies on carbohydrates, while moderate-intensity exercise utilizes fatty acids. Skeletal muscle interacts with the liver and adipose tissue to maintain metabolic homeostasis. This study aimed to compare the adaptive responses of adult and old mice to HIIT and MICT to determine the potential of each regimen to combat age-related muscle weakness and metabolic dysfunction.

The introduction provides a comprehensive overview of the literature on age-related muscle decline, the molecular mechanisms involved, and the beneficial effects of exercise training on skeletal muscle health. It cites numerous studies demonstrating the age-associated decline in mitochondrial function, reduced protein synthesis, insulin resistance, and the beneficial effects of various exercise modalities on these factors. The review highlights the interplay between skeletal muscle metabolism and other organs like the liver and adipose tissue, emphasizing the importance of understanding systemic adaptation to different training regimens.

Adult (5 months) and old (24 months) male C57BL/6J mice were divided into sedentary control, HIIT, and MICT groups. HIIT consisted of three 2-minute runs at 27 m/min with 1-minute rest periods, while MICT involved a single 45-minute run at 13 m/min. Body composition was assessed using NMR. Blood glucose, lactate, and insulin levels were measured. In vivo metabolism was analyzed using indirect calorimetry. Muscle function was evaluated using grip strength and wire hang tests. Electron microscopy examined mitochondrial morphology. Western blotting quantified mitochondrial proteins. Transcriptomics (microarray analysis and qPCR) analyzed gene expression in gastrocnemius muscle. Metabolomics (mass spectrometry) profiled serum and liver metabolites. Statistical analyses included ANOVA, Kruskal-Wallis test, and PLS-DA.

MICT training in old mice resulted in weight loss, decreased body fat, improved glucose regulation, increased voluntary activity, and enhanced neuromuscular performance (increased wire hang time). While HIIT showed less consistent effects. Electron microscopy revealed minor changes in mitochondrial morphology. Western blotting demonstrated increased PGC-1α, SIRT3, and Fis1 in exercised mice, suggesting enhanced mitochondrial biogenesis and mitophagy. Transcriptomic analysis showed that MICT in old mice upregulated pathways related to translation, proteostasis, and RNA splicing, while suppressing inflammatory responses. Metabolomic analysis revealed age-dependent differences in serum and liver metabolites, with MICT in old mice showing enrichment of lipids and amino acids and depletion of glucose metabolites in the liver, suggesting a shift in substrate utilization. Integrated analysis highlighted age as the primary factor differentiating the groups, with MICT showing beneficial effects, particularly in older mice.

The findings demonstrate that MICT is particularly beneficial for older mice, improving both physical performance and metabolic health. The observed changes in mitochondrial function, gene expression, and metabolism suggest that MICT induces a beneficial metabolic reprogramming in aging skeletal muscle. The liver's role in providing metabolic substrates is also highlighted, and the study shows that MICT leads to alterations in liver metabolism that support the increased energy demands of the exercising muscle. These findings are consistent with previous research demonstrating the positive effects of exercise on aging, but provide new insights into the mechanisms involved and the potential benefits of tailored exercise regimens for older individuals.

This study demonstrates that moderate-intensity continuous training (MICT) is a more effective exercise regimen than high-intensity interval training (HIIT) for improving healthspan in aging mice. MICT induced beneficial metabolic and genomic reprogramming in skeletal muscle and liver, suggesting that a tailored approach to exercise may be beneficial for improving health in older individuals. Further research should investigate the effects of these regimens in female mice and explore the role of circadian rhythms in coordinating the response to exercise.

This study was conducted only in male C57BL/6J mice, limiting the generalizability of the findings. The four-week training period may have been insufficient to elicit maximal effects in adult mice. The study did not investigate the impact of exercise on adipose tissue metabolism or the effects of weight loss on the observed outcomes. Longitudinal studies are needed to fully understand the long-term benefits of these exercise regimens.