Carnitine Acetyltransferase Mitigates Metabolic Inertia and Muscle Fatigue during Exercise

Abstract

Acylcarnitine metabolites have gained attention as biomarkers of nutrient stress, but their physiological relevance and metabolic purpose remain poorly understood. Short chain carnitine conjugates, including acetylcarnitine, derive from their corresponding acyl-CoA precursors via the action of carnitine acetyltransferase (CrAT), a bidirectional mitochondrial matrix enzyme. We show here that contractile activity reverses acetylcarnitine flux in muscle, from net production and efflux at rest to net uptake and consumption during exercise. Disruption of this switch in mice with muscle-specific CrAT deficiency resulted in acetyl-CoA deficit, perturbed energy charge and diminished exercise tolerance, whereas acetylcarnitine supplementation produced opposite outcomes in a CrAT-dependent manner. Likewise, in exercise-trained compared to untrained humans, post-exercise phosphocreatine recovery rates were positively associated with CrAT activity and coincided with dramatic shifts in muscle acetylcarnitine dynamics. These findings show acetylcarnitine serves as a critical acetyl buffer for working muscles and provide insight into potential therapeutic strategies for combatting exercise intolerance.

Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart

“…CrAT activity was assayed spectrophotometrically using a 5,5=-dithion-bis-2-nitrobenzoic acid (DTNB) reaction at 412 nm absorbance, as previously described (55). The reaction mixture contained 0.1 M Tris·HCl (pH 8.0), 125 M DTNB, 0.1 mM acetyl-CoA, 1.1 mM L-carnitine, and an aliquot of the enzyme source.…”

“…Given that acetyl-CoA production was increased with maturation, steady-state acetyl-CoA levels would remain the same if its production rates were similar to that of utilization for acetylation. In addition, increased levels of CrAT expression and activity may help keep acetyl-CoA levels for age-dependent increase in lysine acetylation as well as energy demands with maturation because CrAT is shown to supply an acetyl buffer for working skeletal muscles during high workloads (55). Decreased acetylation of PGC-1␣ due to increased acetylation of nuclear GCN5, in conjunction with increased SIRT1 and decreased SIRT6, can enhance cardiac fatty acid oxidation, which is in line with an increase in transcriptional regulation of PPAR␣ and a subsequent increase in LCAD and ␤-HAD.…”

Exercise Inducible Lactate Dehydrogenase B Regulates Mitochondrial Function in Skeletal Muscle

“…The mice were then challenged with 2-min intervals of increasing speed at a 0°incline. The increasing speeds used in the protocol were 10,14,18,22,26,28,30,32,34,36,38, and 40 m/min. The protocol was performed until exhaustion; running distance was derived by calculating the treadmill speed and running time.…”

“…The PGC-1␣ circuit regulates a broad array of genes involved in mitochondrial biogenesis and fuel metabolism (17)(18)(19)(20)(21)(22)(23)(24)(25). Evidence is also emerging that manipulation of metabolic enzyme or metabolite flux in skeletal muscle can significantly affect muscle performance and resistance to fatigue (26,27). We are just beginning to explore the physiological relevance of metabolic enzyme activation and metabolite flux alterations in regulating muscle function.…”

The Acetyl Group Buffering Action of Carnitine Acetyltransferase Offsets Macronutrient-Induced Lysine Acetylation of Mitochondrial Proteins

“…Also related to this general model are recent studies showing that mitochondrial acetyl-CoA balance can be nutritionally regulated via the carnitine-dependent enzyme, carnitine acetyltransferase (CrAT). This enzyme is most abundant in skeletal muscle and heart and localizes to the mitochondrial matrix (Muoio et al, 2012; Noland et al, 2009; Seiler et al, 2015). The freely reversible CrAT reaction interconverts short chain acyl-CoAs and their corresponding carnitine conjugates.…”