The Role of ACLS1 in Maintaining Metabolic Flexibility in Skeletal Muscles

Normal energy metabolism involves periodic shifts in fat and glucose oxidation
according to nutritional and nutritional circumstances. At various levels of physical activity,
the transition from fatty acids or glucose as fuel choice is mediated through a network of cell
signaling and metabolic events that enable effective crosstalk between competing substrates
to maintain energy homeostasis (Goodpaster & Sparks, 2017) . Therefore, metabolic
flexibility refers to the ability of mitochondrial cells to adapt substrate oxidation levels in
response to variations in fuel availability. Conversely, metabolic inflexibility is the inability
to transition between FA and glucose oxidation, which is a key feature of metabolic disorders
such as insulin resistance, type 2 diabetes, and obesity (Li et al., 2014). According to Li et al.
(2014), a key process during FA oxidation is the conversion of FAs to acyl-CoAs by one of
the long-chain acyl-CoA synthetases (ACSLs), which determines whether FAs are used for
complex lipid biosynthesis or oxidation. One of the crucial isoforms of the ACSLs is the
ACSL1, which has been found to play a key role in channeling FAs towards β-oxidation in
highly oxidative tissues. Li et al. (2014) explore whether ACSL1 deficiency in skeletal
muscles impairs exercise endurance and or whole-body fuel metabolism using muscle-
specific Acsl1 knockout mice.

ACSL1 Deficiency Leads to Exercise Intolerance

In Li et al. (2014), ACSL1 deficiency in skeletal muscles impaired fasting glucose
homeostasis. In an overnight fasting challenge, experimental mice were observed to be mildly
hypoglycemic compared to controls (plasma glucose level; 82 ± 6 mg/dL vs. 137 ± 24 mg/dL
in controls). Basal plasma FA concentrations were significantly higher in Acsl1-deficient
mice. In addition, ACSL1 deficiency resulted in more FAs stored in the liver. This means that
the inability of ACSL1 deficient muscle to metabolize FAs resulted in adipose-derived FAs

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being relocated to the liver for storage and re-esterification. Moreover, Acsl1-deficient mice
only run 46-48% of the distance covered by controls in a physical activity challenge.
Moreover, controls had blood glucose values of 87 ± 7 mg/dL despite having depleted liver
glycogen levels. This finding is similar to that of van Loon et al. (2001) whereby total body
fat oxidation rate decreased significantly with increased exercise intensity. In the latter study,
there were no notable changes in substrate utilization within a 55% W max workload, which
could be explained by decreased oxidation rate of plasma FAs.
Metabolic Limitations in Endurance Exercise

Previously, metabolic limitations during endurance exercise have been linked to low
liver glycogen stores, lack of ketone production by the liver, lack of glucose, low
intramuscular fuel reserves, or impaired inability to oxidize fuels (Cox et al., 2016) .
Moreover, there has been increasing interest in the nutritionally-driven metabolism of FAs to
ketone bodies as a way to improve metabolic flexibility during physical exercise. Li et al.
(2014) finding that Acyl-CoAs are minimally available for beta-oxidation in ACSL1
deficiency suggests that nutritional ketone bodies could be an excellent energy source to
improve endurance during exercise, promote the benefits of starvation ketosis, and avoid
metabolic inflexibility (Cox et al., 2016) .
Numerous studies have explored metabolic adaptation in energy use in endurance
sports, such as marathons, and reported markedly increased serum concentrations of mannose
and glucose and the associated concentrations immediately post-marathon. This can be
attributed to the restoration of glycogen stores that were presumably depleted in the early
stages of endurance exercise. Similar to Li et al. (2016), (van Loon et al., 2001) found
extensive lipolysis of triacylglycerols in skeletal muscle, adipose tissue, and the liver during
strenuous exercise due to depletion of intracellular glycogen and glucose stores. Li et. al also
discovered that acyl-CoAs concentration in muscle during endurance exercise increased and

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the source was other ACSL isoforms. However, they could not be converted to acyl-
carnitines or enter the mitochondrial matrix. Therefore, acyl-CoA synthesis by other ACSL
isoforms cannot make up for ACSL1-mediated FA oxidation on skeletal muscle.
Fatty Acid Metabolism and Skeletal Muscle Insulin Resistance
One of the major characteristics of metabolic inflexibility is insulin resistance, which
can develop in various organs and tissues. The most commonly emphasized mechanism
causing insulin resistance in skeletal muscle and the liver is the impaired FA oxidation and
increase accumulation of lipid metabolites including ceramides and diacylglycerol (Smith et
al., 2018) . Most of the rise in glucose metabolism in response to insulin is attributed to the
skeletal muscle, which has been in turn linked to insulin resistance in type 2 diabetes. Li et al.
(2014) reveal that defects in mitochondrial fatty acid oxidation and intramyocellular
accumulation of lipids might be associated with insulin resistance. The absences of ACSL1
resulted in heightened reliance on glucose in muscles, which meant that whole-body glucose
homeostasis was impaired.

Conclusion

Li et al. (2014) findings demonstrate the crucial interdependence of liver and muscle
fuel metabolism. A defect in FA oxidation on skeletal muscle strained glucose supply in the
ACSL1 deficient skeletal muscles. Moreover, these findings are supported by other studies
utilizing both animal and human models with defective fatty acid oxidation. More
importantly, Li et al. (2014) provide an insight into the tissue responsible for systemic insulin
resistance, diabetes, and glucose intolerance. Therefore, skeletal muscle and hepatic insulin
resistance are likely to occur concomitantly.

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