Journal of Cachexia, Sarcopenia and Muscle · 9 authors, 8 centres
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This study demonstrates that dietary phosphate restriction prevents sarcopenia signs in old mice by reducing serum phosphate levels, improving muscle mass, strength, and physical performance. Old mice fed a low-phosphate diet showed 44% more gastrocnemius muscle mass, 52% less fibrotic area, and 30% faster gait speed compared to controls. These findings suggest that lowering phosphate intake could be a potential strategy to prevent age-related muscle deterioration.
**Background:** Sarcopenia is the progressive loss of muscle mass and function associated with aging. Previous work by this group suggested that aging-related hyperphosphataemia is linked to sarcopenia signs. Currently, no effective pharmacological treatments exist beyond resistance exercise. This study investigates whether dietary phosphate restriction or phosphate binders can improve muscle structure and function in aged mice.
**Methods:** Male C57BL6 mice were used across three age groups: young (5 months), old (24 months), and geriatric (28 months). Old and geriatric mice were fed either a standard diet (0.6% phosphate) or a low-phosphate diet (0.2% phosphate) for 3 or 7 months, respectively. A separate group of old mice received the phosphate binder sucroferric oxyhydroxide (Velphoro® 5%) mixed with standard diet for 3 months. Muscle mass was assessed by weighing gastrocnemius and tibialis muscles. Muscle quality was evaluated using nuclear magnetic resonance imaging (NMRI) measuring T2 relaxation time, magnetization transfer (MT), and mean diffusivity (MD). Histological analyses included haematoxylin and eosin staining for fibre cross-sectional area (FCSA), succinate dehydrogenase staining for oxidative fibres, myosin heavy chain staining for fibre typing, and Sirius red staining for fibrosis. Muscle strength was measured by grip test and electrical stimulation of the common peroneal nerve (twitch force, tetanic force, fatigue resistance). Physical performance was assessed via gait analysis (speed, stride length, hind paw base width) and static rod test (orientation time, transition time). Statistical analysis used multilevel linear mixed effects models with cage and cohort adjustments.
**Key Results:** Old mice had significantly higher serum phosphate (21.24 ± 0.95 mg/dL) than young mice (16.46 ± 0.77 mg/dL). Low-phosphate diet reduced serum phosphate to 17.46 ± 0.82 mg/dL in old mice. Old mice on low-phosphate diet showed 44% more gastrocnemius muscle mass (P = 0.004) compared to old controls. NMRI revealed significant improvements: reduced T2 relaxation time (P = 0.014), increased MT (P = 0.045), and increased MD (P = 0.045) in low-phosphate diet mice. Fibre size was increased and fibrotic area reduced by 52% (P = 0.002). Atrogin-1 expression was lower in low-phosphate diet mice. Twitch force (P = 0.004) and tetanic force (P = 0.014) were significantly increased. Gait speed improved by 30% (P = 0.032) and transition time in the static rod test decreased by 55% (P = 0.012). Similar improvements were seen with Velphoro® treatment. In geriatric mice (28 months), low-phosphate diet improved muscle strength and physical performance but did not increase muscle mass. Serum phosphate levels correlated negatively with gastrocnemius mass (r = -0.390, P = 0.001), tetanic force (r = -0.682, P < 0.001), and gait speed (r = -0.534, P < 0.001), and positively with fibrosis (r = 0.398, P = 0.020) and transition time (r = 0.491, P < 0.001).
**Clinical Implications:** This study provides preclinical evidence that hyperphosphataemia contributes to sarcopenia and that dietary phosphate restriction or phosphate binders may prevent age-related muscle deterioration. The findings support the potential of phosphate-lowering strategies as therapeutic interventions for sarcopenia, though clinical studies in humans are needed to confirm translatability. The results are particularly relevant given the lack of effective pharmacological treatments for sarcopenia beyond resistance exercise.