Objective: Older patients are frequently subjected to prolonged hospitalization and extended bed rest, with a negative effect on physical activity and caloric intake. This results in a consistent loss of muscle mass and function, which is associated with functional decline and high mortality. Furthermore, acute muscle disuse can precipitate sarcopenia, defined as the age-dependent loss of muscle mass and function. The aim of this study was to investigate the effect of oral amino acid (AA) supplementation in acute immobilization. We also aimed to characterize the effect and mechanism of the AA mixture in a rodent model of skeletal muscle atrophy, focusing on mitochondrial function. Methods: In the human study, hospitalized older patients (69-87) were included in the control group (n = 50) or were administered 25 g of AA mixture (n = 44) twice daily throughout 7 d of low mobility. We collected data related to length of stay as primary outcome measure. In-hospital mortality, 90-d post-discharge mortality, 90-d post-discharge rehospitalization, and falls also were considered. Moreover, variations of anthropometric measures, body composition and muscle architecture/strength, circulating interleukins, and oxidative stress markers between the beginning and the end of the supplementation period were analyzed as secondary outcomes. In the animal study, C57/Bl6 mice underwent immobilization of one hindlimb by stapling the foot exploiting normal dorsotibial flexion. Age-matched mice that never had their hindlimbs immobilized were used as controls. Sub-groups of mice subjected to the immobilization procedure were administered the AA mixture in drinking water (I+A) and were compared to a placebo group (I+P). After 10 days, muscle function was studied by both endurance running and grip strength tests. Tibialis anterior (TA) muscles were excised and used for mitochondrial isolation. 2 Results: Similar values were reported between the two groups regarding age, body weight, and body mass index. Although no difference in terms of in-hospital, 90-d post-discharge, or overall mortality rate was observed between the two groups, a reduction in length of stay, 90-d post-discharge hospitalization, and falls was observed in the AA supplementation group rather than in controls. Furthermore, the AA mixture limited muscle architecture/strength impairment and circulating oxidative stress, which occurred during hospitalization-related bed rest. The latter data was associated with increased circulating levels of anti-inflammatory cytokines interleukin-4 and -10. In animals, hindlimb immobilization reduced maximal running times and distances, along with limb grip strength; however, the extent of reduction was lower in I+A than I+P mice. Immobilization resulted in TA atrophy, characterized by a reduction in both wet weight and TA/body weight ratio. Interestingly, these alterations were slightly observed in mice treated with the AA mixture. The mitochondrial yield from TA of I+P mice was lower than controls; of note, the mitochondrial yield from TA of I+A animals was similar to controls. AA mixture administration also preserved mitochondrial bioenergetics and oxidative damage in TA muscle, which was disrupted in I+P mice with respect to controls. Conclusions: These results suggest that the AA mixture limits several alterations associated with low mobility in older hospitalized patients, such as length of stay, 90-d post-discharge hospitalization, and falls, preventing the loss of muscle function, as well as the increase of circulating interleukins and oxidative stress markers. Furthermore, this study demonstrates that the AA mixture prevents loss of muscle mass and function in skeletal muscle atrophy by protecting mitochondria. Other than providing a further link between mitochondria and proteostatic maintenance to muscle atrophy, these results encourage further research aimed at targeting mitochondria to treat sarcopenia.

Effect of amino acid supplementation on skeletal muscle during acute immobilization in hospitalized elderly subjects: possible impact on mitochondria

LO BUGLIO, AURELIO
2021-01-01

Abstract

Objective: Older patients are frequently subjected to prolonged hospitalization and extended bed rest, with a negative effect on physical activity and caloric intake. This results in a consistent loss of muscle mass and function, which is associated with functional decline and high mortality. Furthermore, acute muscle disuse can precipitate sarcopenia, defined as the age-dependent loss of muscle mass and function. The aim of this study was to investigate the effect of oral amino acid (AA) supplementation in acute immobilization. We also aimed to characterize the effect and mechanism of the AA mixture in a rodent model of skeletal muscle atrophy, focusing on mitochondrial function. Methods: In the human study, hospitalized older patients (69-87) were included in the control group (n = 50) or were administered 25 g of AA mixture (n = 44) twice daily throughout 7 d of low mobility. We collected data related to length of stay as primary outcome measure. In-hospital mortality, 90-d post-discharge mortality, 90-d post-discharge rehospitalization, and falls also were considered. Moreover, variations of anthropometric measures, body composition and muscle architecture/strength, circulating interleukins, and oxidative stress markers between the beginning and the end of the supplementation period were analyzed as secondary outcomes. In the animal study, C57/Bl6 mice underwent immobilization of one hindlimb by stapling the foot exploiting normal dorsotibial flexion. Age-matched mice that never had their hindlimbs immobilized were used as controls. Sub-groups of mice subjected to the immobilization procedure were administered the AA mixture in drinking water (I+A) and were compared to a placebo group (I+P). After 10 days, muscle function was studied by both endurance running and grip strength tests. Tibialis anterior (TA) muscles were excised and used for mitochondrial isolation. 2 Results: Similar values were reported between the two groups regarding age, body weight, and body mass index. Although no difference in terms of in-hospital, 90-d post-discharge, or overall mortality rate was observed between the two groups, a reduction in length of stay, 90-d post-discharge hospitalization, and falls was observed in the AA supplementation group rather than in controls. Furthermore, the AA mixture limited muscle architecture/strength impairment and circulating oxidative stress, which occurred during hospitalization-related bed rest. The latter data was associated with increased circulating levels of anti-inflammatory cytokines interleukin-4 and -10. In animals, hindlimb immobilization reduced maximal running times and distances, along with limb grip strength; however, the extent of reduction was lower in I+A than I+P mice. Immobilization resulted in TA atrophy, characterized by a reduction in both wet weight and TA/body weight ratio. Interestingly, these alterations were slightly observed in mice treated with the AA mixture. The mitochondrial yield from TA of I+P mice was lower than controls; of note, the mitochondrial yield from TA of I+A animals was similar to controls. AA mixture administration also preserved mitochondrial bioenergetics and oxidative damage in TA muscle, which was disrupted in I+P mice with respect to controls. Conclusions: These results suggest that the AA mixture limits several alterations associated with low mobility in older hospitalized patients, such as length of stay, 90-d post-discharge hospitalization, and falls, preventing the loss of muscle function, as well as the increase of circulating interleukins and oxidative stress markers. Furthermore, this study demonstrates that the AA mixture prevents loss of muscle mass and function in skeletal muscle atrophy by protecting mitochondria. Other than providing a further link between mitochondria and proteostatic maintenance to muscle atrophy, these results encourage further research aimed at targeting mitochondria to treat sarcopenia.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11369/425212
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