Background: Skeletal muscle integrates many of the systemic signals, which contribute to the adaptive remodeling, and beneficial effects of exercise. One mechanism through which muscle mediates the systemic effects of exercise is through muscle-derived hormones known as myokines. We identified the metabolite β-aminoisobutyric acid (BAIBA) as an exercise-mediated small molecule myokine. BAIBA is secreted from muscle in response to increased expression of the transcriptional co-regulator PGC-1α, a master regulator of the muscle adaptive response to exercise. However, how BAIBA functions to regulate the adaptive responses of skeletal muscle to exercise remains poorly understood.
Methods: 8-week-old male C57BL/6J mice (n=20) were randomly assigned to receive either a chow diet or a chow diet supplemented with 100mg/kg/day of β-aminoisobutyric acid (BAIBA) in their drinking water for 6 weeks. At the end of the study, the right soleus muscles were assessed in situ for force and fatigability; and for oxygen consumption using Oxygraph-2K high-resolution respirometers. The expression of genes associated with fibre-type was evaluated using RT-qPCR in fully differentiated primary human myotubes. The role of PPARδ was investigated using siRNA techniques. Two way ANOVA was performed for statistical analysis. P-value nominal significance will be p< 0.05.
Results: We show that BAIBA improves muscle metabolism, exercise efficiency and performance in mice. Oxygen consumption (VO2) and energy expenditure are increased in BAIBA-treated mice. Furthermore, BAIBA increased soleus in situ muscle contractile force (p=0.0004), fatigue resistance (p=0.0063), mitochondrial number and function. We found that BAIBA drives muscle fibre-type switching to an oxidative phenotype. BAIBA increased expression of PPARδ (p=0.0001, n=4/group), and genes determining muscle fibre-type, including Myosin Heavy Chain 7 (MYH7) (type I muscle) (p=0.0001 n=4/group), Myosin Heavy Chain 2 (MYH2) (type IIA intermediate muscles) (p=0.0046, n=4/group) in fully differentiated primary human myotubes. BAIBA regulates specific fibre-type gene expression in human myocytes through PPARδ.
Conclusion: Our findings demonstrate that BAIBA is a key paracrine myokine, which, in part, regulates the effects of exercise to improve muscle function with resultant effects on exercise performance.
Keywords: BAIBA, skeletal muscle adaptation, exercise performance, PPARδ, oxidative phenotype, fibre-type switching.