Cardio-Sarcopenia Unveiled: Metabolic Coupling of Phenylalanine and BAIBA in Skeletal– Cardiac Muscle Dysfunction

Study Objective: To investigate the phenylalanine (Phe)-β-aminoisobutyric acid (BAIBA) metabolic axis as a mechanistic driver and therapeutic target in age-related cardio-sarcopenia. Hypothesis: Elevated circulating Phe induces mitochondrial dysfunction, oxidative stress, and cellular senescence in both cardiac and skeletal muscle, contributing to concurrent cardiac remodeling and sarcopenia. BAIBA supplementation mitigates Phe-induced toxicity and restores muscle quality and cardiac function through mitochondrial biogenesis and anti-inflammatory pathways. Methodology: We leveraged a community cohort study, the Arlington Study on Healthy Aging (ASHA; n=400, age 55-85) to quantify plasma Phe and BAIBA by LC-MS/MS and test associations with cardiac structure (LV mass, concentricity) via MRI, skeletal muscle quality (myosteatosis, thigh muscle density) via MRI, and physical performance (6-minute walk, SPPB, grip strength). We further used cardiac and skeletal muscle cells to investigate the cellular effects of phenylalanine and developed a new MS-LC/MS analytical method to accurately quantify Phe across all samples in our study. All cellular experiments were performed with ≥3 biological replicates × ≥3 technical replicates per condition, and comparisons between different groups used one-way or two-way ANOVA with Tukey's post-hoc tests. Statistical significance was set at two-tailed α=0.05. Results: Building on our initial discovery using Raman spectroscopy, which revealed that the tibialis anterior muscle from old mice showed a marked increase in the Phe spectral peak (~1,600 cm - ¹) alongside broader biochemical remodeling in protein and phospholipid signatures. Subsequently, we developed an LC-MS/MS method to detect Phe in biological samples, which was applied to our serum analysis from aged individuals. Preliminary human data (n=10) demonstrate higher serum Phe levels in individuals with high fat % (p< 0.0005), which correlate strongly and positively with intramuscular fat infiltration (myosteatosis) in the thigh (Quadriceps fat %: r = 0.78, p < 0.023, Hamstrings fat %: r = 0.88, p < 0.004, total thigh muscle fat %: r = 0.88, p < 0.0042). The same individuals with elevated Phe and myosteatosis showed significantly reduced physical function, as indicated by lower SPPB scores (p< 0.008) and 6-minute walk distance (p< 0.048). Further, Phe levels were also associated with subclinical cardiac remodeling markers indicated by increased LV mass (indexed to BSA): r = 0.67, p < 0.048, reduced LV stroke volume (indexed to BSA): r = –0.57, p = 0.1), elevated systolic blood pressure: r = 0.66, p < 0.053, and higher concentricity index (concentric remodeling pattern): r = 0.71, p < 0.05. Finally, our cellular data showed that co-treatment of cardiomyocytes and skeletal myocytes with BAIBA (10–20 μM) mitigates or reverses Phe-induced apoptosis and impaired differentiation. RNA-seq data indicated that BAIBA treatment robustly upregulates metabolic, mitochondrial, and stress-adaptive genes and downregulates NF-κB pathway (Icam1, Ifn-γ, and Tnf-α) and exerts a protective function. Conclusions: This study establishes the Phe-BAIBA axis as a novel, modifiable metabolic pathway linking cardiac and skeletal muscle aging. BAIBA represents a first-in-class exercise-mimetic therapeutic for cardio-sarcopenia, addressing an unmet clinical need in 20-40% of older adults. This abstract was presented at the American Physiology Summit 2026 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.