Upcycled porcine whole-blood protein hydrolysate attenuates age-related sarcopenia-like phenotypes in Caenorhabditis elegans in an RSKS-1-dependent manner.
It is shown that PWBPH delays sarcopenia-like phenotypes in aging C. elegans, associated with preserved mitochondrial status and stress resilience, and support further evaluation of PWBPH as a food-derived, upcycled peptide ingredient for muscle health span.
Abstract
Sarcopenia is an age-associated loss of muscle mass and function that increases the risk of frailty, disability, and mortality, yet there are no FDA-approved agents specifically indicated for sarcopenia. Porcine whole-blood protein hydrolysate (PWBPH), an upcycled protein resource from slaughter by-products, has been proposed to support muscle-related outcomes, but whether it mitigates functional deterioration during physiological aging and which regulatory programs are required remain unclear. PWBPH was enriched in essential amino acids and comprised low-molecular-weight peptides (<1 kDa). Here, we evaluated PWBPH in Caenorhabditis elegans as an in vivo model of muscle aging. Chronic exposure to a low dose of PWBPH (0.01%, w/v) from early adulthood attenuated age-dependent functional decline, as assessed by pharyngeal pumping, swimming performance, and locomotor activity. PWBPH mitigated age-associated myosin loss and preserved mitochondrial network integrity. Consistently, PWBPH maintained ATP content and mitochondrial DNA copy number (a proxy for mitochondrial content), and blunted the age-induced upregulation of mitochondrial stress-response transcripts. PWBPH also improved locomotor resistance to acute oxidative challenge (H2O2). Notably, these benefits were abolished in rsks-1 mutants, the C. elegans ortholog of ribosomal protein S6 kinase (S6K), indicating that RSKS-1/S6K is genetically required for PWBPH-mediated protection. Collectively, our findings show that PWBPH delays sarcopenia-like phenotypes in aging C. elegans, associated with preserved mitochondrial status and stress resilience, and support further evaluation of PWBPH as a food-derived, upcycled peptide ingredient for muscle health span.
Sarcopenia, characterized by an age-related progressive decline in skeletal muscle mass and strength, is emerging as a major public health concern in aging societies. Despite growing insights into sarcopenia pathophysiology, effective and targeted therapeutic strategies for preventing or treating age-related muscle loss remain limited. Here, we aimed to examine the effects of Weissella cibaria Wikim0187, a probiotic strain isolated from kimchi, on age-related sarcopenia. Male C57BL/6J mice aged 18 months received oral administration of Wikim0187 (1 × 109 CFU per mouse) for 4 months. Wikim0187 supplementation induced significant increases in gastrocnemius muscle mass and quadriceps muscle mass, absolute grip strength, and mean muscle fiber cross-sectional area. At the molecular level, MuRF-1 and Atrogin-1 expression was substantially reduced, whereas that of MyoD and Myogenin was markedly elevated, particularly in the quadriceps muscle. Western blot analysis confirmed a reduction in Atrogin-1 protein levels and an increase in phosphorylated Akt. In addition, gut microbiota analysis revealed significant alterations in microbial composition, with positive correlations between enriched bacterial taxa and improved clinical parameters. Taken together, these findings support the therapeutic potential of Wikim0187 as a safe and effective intervention for the prevention and treatment of sarcopenia in elderly populations.
Sulhee Lee, Gahee Choi, Sang-Pil Choi et al.· Journal of Microbiology and...· 0 citations
Protein utilization efficiency is a key determinant of metabolic health, body composition, and muscle function, particularly under high-protein dietary conditions and when using plant-based protein sources with lower digestibility. However, the extent to which enhancing early gastric proteolysis translates into improved whole-body protein utilization remains unclear. The present in vivo study investigated whether supplementation with an actinidin-enriched kiwifruit concentrate (Kwd+®) modulates protein utilization efficiency and physiological outcomes under normoproteic and hyperproteic dietary conditions using casein or pea protein as dietary sources. Rats were fed normoproteic casein (NP), high-protein casein (CHP), or high-protein pea (PHP) diets with or without Kwd+® supplementation for 8 weeks. Gastric protein hydrolysis patterns were evaluated by SDS–PAGE, while metabolic outcomes were assessed through body composition, plasma amino acid profiling, skeletal muscle morphology, and contractile function. Kwd+® supplementation enhanced gastric proteolysis in a protein source-dependent manner. Despite the absence of significant changes in circulating amino acid concentrations after multiple comparison correction, Kwd+® improved markers of protein utilization efficiency depending on dietary protein source. In animals fed a high-protein pea diet, supplementation significantly reduced fat mass relative to accumulated protein intake, indicating improved nutrient partitioning. In contrast, in animals fed a high-protein casein diet, Kwd+® increased muscle mass relative to protein intake, suggesting enhanced anabolic efficiency. Under normoproteic conditions, Kwd+® supplementation was associated with an increased muscle fiber cross-sectional area and improved fatigue resistance without alterations in fiber type composition or contractile protein abundance. These findings demonstrate that modulation of early gastric proteolysis through actinidin produces protein source-dependent effects on protein utilization efficiency, nutrient partitioning, and muscle function. This work highlights a novel nutritional strategy to improve metabolic outcomes and muscle performance, particularly in the context of high-protein and plant-based diets.
Iván Benito-Vázquez, Pablo Méndez-Albiñana, Aaron Fernández-Quintero et al.· International Journal of Mol...· 0 citations
Background/Objectives: Sarcopenia involves a gradual decline in skeletal muscle mass that may occur during aging or in association with chronic pathological conditions. It markedly reduces muscle strength and mobility, thereby impairing quality of life. Because sarcopenia’s severity directly correlates with frailty, it represents an important predictor of prognosis and disease risk. Current preventive and therapeutic strategies rely mainly on physical activity, which is not feasible for all patients. This study investigated the biological effects of two independently prepared Tuber borchii (T. borchii) extracts in an in vitro model of sarcopenic stress. Methods: The activity of T. borchii extracts was investigated in a cell-based model of sarcopenia, following previous observations that these preparations influence proliferation-related pathways, including ERK1/2 phosphorylation. Specifically, differentiated myotubes were exposed to D-galactose to reproduce atrophy-associated cellular changes, and the impact of T. borchii extracts on protein synthesis, turnover, and cell morphology was assessed. Results: T. borchii extracts enhanced protein synthesis and turnover in myotubes. Furthermore, the treatment significantly reduced the expression of key galactose-induced sarcopenia and atrophy markers, such as MuRF1. Morphological analysis confirmed this protective effect, showing that treated myotubes maintained greater thickness and exhibited a larger cross-sectional area despite exposure to the sarcopenic stimulus. Conclusions: These results indicate that T. borchii extracts can attenuate selected cellular alterations associated with muscle aging. Future identification of the most active components may support their development as nutraceutical supplements.
Vincenzo Aiello, L. Lupacchini, M. Belli et al.· Nutrients· 0 citations
BACKGROUND
Sarcopenia is a progressive muscle-wasting condition driven in part by chronic inflammation; however, the specific inflammatory mediators that contribute to functional decline in humans and their responses to exercise remain poorly defined.
METHODS
We analyzed public ribonucleic acid (RNA) datasets to identify inflammatory pathways associated with aging and exercise. Additionally, we validated candidate factors in older adults through 2 human studies. Complementary cellular and animal experiments were performed to dissect the mechanistic responses to muscle atrophy, injury, and exercise-mimetic therapies.
RESULTS
C-X-C motif chemokine ligand 2 (CXCL2) was identified as a prominent age-associated exercise-responsive inflammatory factor in human datasets. In older adults, plasma CXCL2 levels increased with sarcopenia severity and correlated with SPS-defined functional impairment (r = 0.6472, p = 0.0003). In the 48-week human intervention, structured exercise substantially improved strength, mobility, and endurance and markedly reduced circulating CXCL2 (p < 0.0001) and tumor necrosis factor-alpha (TNF-α) levels (p < 0.0001). In contrast, individuals in the non-exercise group exhibited progressive functional decline and increased cytokine levels. Moreover, Cxcl2 expression was upregulated in the skeletal muscles of aged mice and induced by muscle atrophy or injury (p = 0.0082). In contrast, exercise-mimetic stimulation and acute endurance exercise suppressed Cxcl2 expression (p = 0.0148, p = 0.0072). Importantly, blocking CXCL2-CXCR2 signaling attenuated dexamethasone-induced expression of the atrophy markers Fbxo32 (p = 0.0336, 0.0127, 0.0061) and Trim63 (p = 0.0296, 00160, 0.0042).
CONCLUSION
Human evidence from year-long clinical exercise interventions, supported by transcriptomic, cellular, and animal experiments, identified CXCL2 as a modifiable inflammatory mediator linking aging to muscle atrophy. Consistent suppression of CXCL2 by exercise and attenuation of atrophic signaling through CXCR2 inhibition highlights the CXCL2-CXCR2 axis as a promising target for mitigating sarcopenia.
Juyeon Lee, Sung-Wook Chun, Subin Choi et al.· Journal of Sport and Health...· 0 citations
Sarcopenia is characterized by the progressive loss of skeletal muscle mass and strength, accompanied by impaired regenerative capacity. This study examined age-related changes in skeletal muscle regeneration and the associated expression of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and myogenin (MyoG). Male C57BL/6 mice aged 3, 13, and 23 months were subjected to barium chloride (BaCl2)-induced tibialis anterior muscle injury. In parallel, C2C12 cells were exposed to repeated low-dose hydrogen peroxide (H2O2) to induce senescence-associated changes under oxidative stress, and the effect of the TWEAK inhibitor L524 was evaluated. Muscle mass and grip strength showed age-dependent declines. Following BaCl2 injury, MyoD expression was induced similarly across age groups, whereas MyoG and embryonic myosin heavy chain expression significantly decreased with advancing age. TWEAK expression increased in injured muscle with age, while p-4E-BP1 showed no clear age-dependent change. In C2C12 cells, repeated H2O2 exposure at 100 μM, which maintained cell viability above 90%, induced senescence-associated changes, reduced myotube formation, increased TWEAK expression, and decreased MyoG expression, whereas treatment with the TWEAK inhibitor L524 attenuated the H2O2-associated reduction in MyoG expression. Collectively, these findings suggest that TWEAK signaling may be associated with oxidative stress and age-related impairments in muscle regeneration.
Jin-Hwa Kim, Hyun-Tae Kim, Jeong-won Kim et al.· Experimental Gerontology· 0 citations
Age‐related sarcopenia is characterized by a progressive decline in skeletal muscle mass and function, with satellite cell dysfunction representing a central pathogenic mechanism. Diosgenin, a steroidal saponin derived from plants of the Dioscorea genus, has demonstrated potential anti‐aging properties; however, its role in sarcopenia remains unclear. In this study, naturally aged C57BL/6J mice and a D‐galactose (D‐gal)–induced senescent C2C12 cell model were employed to systematically investigate the effects of diosgenin on muscle function, satellite cell dynamics, and the sirtuin 1 (SIRT1)/peroxisome proliferator‐activated receptor gamma coactivator‐1 alpha (PGC‐1α) signaling pathway. Diosgenin treatment significantly improved forelimb grip strength and exercise endurance, increased the gastrocnemius muscle index, and enlarged muscle fiber cross‐sectional area in aged mice. Mechanistically, diosgenin upregulated the expression of myokines meteorin‐like protein (METRNL) and insulin‐like growth factor 1 (IGF‐1) at both mRNA and protein levels, increased the number of proliferative satellite cells positive for paired box 7 (Pax7) and Ki67, and enhanced the expression of myogenic markers, including myogenic factor 5 (Myf5), Pax7, and myosin heavy chain II (MyHC II). These effects were mediated by direct activation of SIRT1, leading to deacetylation of PGC‐1α. Notably, pharmacological inhibition of SIRT1 with EX527 markedly abrogated the diosgenin‐induced effects. Molecular docking and cellular thermal shift assays further confirmed the direct interaction between diosgenin and SIRT1. Collectively, these findings demonstrate that diosgenin alleviates age‐related sarcopenia by activating the SIRT1/PGC‐1α signaling pathway to promote satellite cell proliferation and myogenic differentiation, highlighting its potential as a promising therapeutic candidate for sarcopenia.
Xin Zeng, Han-Wen Ding, Ziye Li et al.· Aging Cell· 0 citations
