The effects of age and exercise training on lysosomal adaptations within skeletal muscle

Skeletal muscle mass comprises a large fraction (~40%) of the total human body mass, making it an essential contributor to overall physical health. Mitochondria are responsible for the metabolic status of skeletal muscle due to their ability to adapt to various physiological conditions. The aging population undergoes a loss of skeletal muscle mass, strength, and function, termed sarcopenia. The maintenance of a healthy mitochondrial pool is imperative for the preservation of muscle mass and metabolic health with age. The important removal of dysfunctional mitochondria happens via the process of mitophagy in which these organelles are tagged for degradation, engulfed and delivered to lysosomes, representing the vital role lysosomes play in the turnover of mitochondria. If lysosomes become defective with age, this can contribute to the accumulation of defective mitochondria. Thus, we have investigated lysosomes to understand their role in aging and exercise. We hypothesize that lysosome content will increase with age, but that lysosome proteolytic function will be diminished, and that exercise training will serve to restore this functionality in aged muscle. We studied these adaptations in skeletal muscle from young (5-7 months) and aged (21-23 months) mice following a 6-week voluntary wheel running (VWR) protocol compared to an untrained group. During the training protocol, the aged group ran significantly less than the young group. Despite this, training attenuated the aging-induced loss of muscle mass, especially in the predominantly slow-twitch soleus muscle. During an acute exhaustive bout of exercise, young and old trained groups ran significantly more time than untrained groups, indicating the effectiveness of the training to induce adaptative changes. Lysosomal protein yield was 2-fold greater in the aged, compared to the young cohorts, and this was accompanied by 1.5-fold, 2-fold and 2-fold increases in Lamp1, mature cathepsin D and precursor cathepsin B in aged muscle respectively. Lysosome proteolytic function, assessed in purified lysosomal fractions, was reduced by ~30 % in aged muscle. Remarkably, training improved lysosomal function in both young (1.3- fold) and old (1.5-fold) muscle. Thus, our results showed that aged mice have increased lysosomal protein content while displaying a more dysfunctional organelle pool. The chronic exercise protocol induced mitigation of these changes, illustrating the potential of improved clearance of dysfunctional cargo, including mitochondria, via enhanced proteolytic capacity of lysosomes, thereby improving muscle health with age. Supported by NSERC Canada. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.