Dietary phosphate restriction prevents the appearance of sarcopenia signs in old mice

Abstract

Background Sarcopenia is defined by the progressive and generalized loss of muscle mass and function associated with aging. We have previously proposed that aging-related hyperphosphataemia is linked with the appearance of sarcopenia signs. Because there are not effective treatments to prevent sarcopenia, except for resistance exercise, we propose here to analyse whether the dietary restriction of phosphate could be a useful strategy to improve muscle function and structure in an animal model of aging. Methods Five-month-old (young), 24-month-old (old) and 28-month-old (geriatric) male C57BL6 mice were used. Old and geriatric mice were divided into two groups, one fed with a standard diet (0.6% phosphate) and the other fed with a low-phosphate (low-P) diet (0.2% phosphate) for 3 or 7 months, respectively. A phosphate binder, Velphoro®, was also supplemented in a group of old mice, mixed with a standard milled diet for 3 months. Muscle mass was measured by the weight of gastrocnemius and tibial muscles, and quality by nuclear magnetic resonance imaging (NMRI) and histological staining assays. Muscle strength was measured by grip test and contractile properties of the tibialis muscle by electrical stimulation of the common peroneal nerve. Gait parameters were analysed during the spontaneous locomotion of the mice with footprinting. Orientation and motor coordination were evaluated using a static rod test. Results Old mice fed with low-P diet showed reduced serum phosphate concentration (16.46 ± 0.77 mg/dL young; 21.24 ± 0.95 mg/dL old; 17.46 ± 0.82 mg/dL low-P diet). Old mice fed with low-P diet displayed 44% more mass in gastrocnemius muscles with respect to old mice (P = 0.004). NMRI revealed a significant reduction in T2 relaxation time (P = 0.014) and increased magnetization transfer (P = 0.045) and mean diffusivity (P = 0.045) in low-P diettreated mice compared with their coetaneous. The hypophosphataemic diet increased the fibre size and reduced the fibrotic area by 52% in gastrocnemius muscle with respect to old mice (P = 0.002). Twitch force and tetanic force were significantly increased in old mice fed with the hypophosphataemic diet (P = 0.004 and P = 0.014, respectively). Physical performance was also improved, increasing gait speed by 30% (P = 0.032) and reducing transition time in the static rod by 55% (P = 0.012). Similar results were found when diet was supplemented with Velphoro®. Conclusions The dietary restriction of phosphate in old mice improves muscle quantity and quality, muscle strength and physical performance. Similar results were found using the phosphate binder Velphoro®, supporting the role of phosphate in the impairment of muscle structure and function that occurs during aging.

Skeletal Muscle Injury in Chronic Kidney Disease—From Histologic Changes to Molecular Mechanisms and to Novel Therapies

“…Phosphate levels rise during aging, and it has been shown that in aged mice elevated serum phosphate levels associate with reduced muscle strength [262,263]. Furthermore, aged mice receiving a low-phosphate diet show improved muscle function, with larger myofiber area, less fiber type switching, and reduced fibrosis, as well as increased muscle strength and physical performance [263,264]. Combined, these in vivo studies suggest that rises in extracellular phosphate level can impair the myogenesis and the growth of myofibers, alter metabolic activity of skeletal muscle tissue, and promote inflammation.…”

“…Finally, administration of a low-phosphate diet has been shown to improve skeletal muscle atrophy in Col4a3 −/− mice [110], suggesting that in this CKD model the injury might be caused by the hyperphosphatemia. Furthermore, phosphate levels rise during aging, and it has been shown that aged mice receiving a low-phosphate diet have improved muscle function, with a larger cross-sectional area of myofibers and reduced fibrosis [264]. Future human studies should determine the potential protective effects of a low-phosphate diet on skeletal muscle tissue in CKD patients or the elderly.…”

Can a Low-Phosphate Diet for Chronic Kidney Disease Treat Cancer? An Interdisciplinary Literature Review

“…For example, in 2018, researchers from the Republic of China found that serum phosphate levels within the high end of the normal range were associated with age-related loss of muscle strength, or dynapenia, in an analysis of U.S. NHANES data [91]. Additionally, a 2023 study in the Journal of Cachexia, Sarcopenia and Muscle found that feeding geriatric mice a low-phosphate diet lowered the serum phosphate of the mice to levels approaching serum levels in younger mice [92]. Remarkably, compared to geriatric mice fed a standard diet three-times higher in phosphate, the muscle mass measured in the gastrocnemius and tibialis of the geriatric mice receiving the low-phosphate diet increased by 44%, along with increases in strength and physical performance.…”

Ageing of skeletal muscle extracellular matrix and mitochondria: finding a potential link

“…The expression of atrogin‐1 in old animals fed with the low‐phosphate diet is lower. In addition, skeletal muscle fibrotic regions in aged mice fed with a low-phosphate diet showed a considerable reduction, suggesting that age-related fibrosis could be delayed by a decreased serum phosphate concentration [ 215 ].…”