Resting skeletal muscle PNPLA2 (ATGL) and CPT1B are associated with peak fat oxidation rates in men and women but do not explain observed sex differences

Abstract

We explored key proteins involved in fat metabolism that might be associated with peak fat oxidation (PFO) and account for sexual dimorphism in fuel metabolism during exercise. Thirty-six healthy adults [15 women; 40 ± 11 years of age; peak oxygen consumption 42.5 ± 9.5 ml (kg body mass) -1 min -1 ; mean ± SD] completed two exercise tests to determine PFO via indirect calorimetry. Resting adipose tissue and/or skeletal muscle biopsies were obtained to determine the adipose tissue protein content of PLIN1, ABHD5 (CGI-58), LIPE (HSL), PNPLA2 (ATGL), ACSL1, CPT1B and oestrogen receptor α (ERα) and the skeletal muscle protein content of FABP 3 (FABPpm), PNPLA2 (ATGL), ACSL1, CTP1B and ESR1 (ERα). Moderate strength correlations were found between PFO [in milligrams per kilogram of fat-free mass (FFM) per minute] and the protein content of PNPLA2 (ATGL) [r s = 0.41 (0.03-0.68), P < 0.05] and CPT1B[r s = 0.45 (0.09-0.71), P < 0.05] in skeletal muscle. No other statistically significant bivariate correlations were found consistently. Females had a greater relative PFO than males [7.1 ± 1.9 vs. 4.5 ± 1.3 and 7.3 ± 1.7 vs. 4.8 ± 1.2 mg (kg FFM) -1 min -1 in the adipose tissue (n = 14) and skeletal muscle (n = 12) subgroups, respectively (P < 0.05)].No statistically significant sex differences were found in the content of these proteins.The regulation of PFO might involve processes relating to intramyocellular triglyceride hydrolysis and mitochondrial fatty acid transport, and adipose tissue is likely to play a more minor role than muscle. Sex differences in fat metabolism are likely to be attributable to factors other than the resting content of proteins in skeletal muscle and adipose tissue relating to triglyceride hydrolysis and fatty acid transport.

Peak fat oxidation is positively associated with vastus lateralis CD36 content, fed-state exercise fat oxidation, and endurance performance in trained males

“…Previous research has observed relationships between PFO and CS activity and other mitochondrial markers, such as mitochondrial volume density and OXPHOS subunit protein content (Nordby et al 2006 ; Stisen et al 2006 ; Dandanell et al 2018 ; Shaw et al 2020 ). The positive association between PFO and vastus lateralis CD36 abundance in the present investigation is to our knowledge a novel observation (Table 2 ), and adds to recent research reporting associations between PFO and abundance of FABPpm and CPT1B (Chrzanowski-Smith et al 2021 ). It is likely the relationship between PFO and whole-muscle CD36 abundance is explained by capacity for CD36 translocation, given CD36 translocates to the sarcolemmal (Bradley et al 2012 ) and mitochondrial (Holloway et al 2006 ) membranes during exercise to facilitate fatty acid import.…”

“…Associations have been observed between PFO and various skeletal muscle characteristics, including type I fibre percentage and capillary density, mitochondrial protein content and enzyme activities, and enzymes involved in β -oxidation and intramuscular triacylglycerol hydrolysis (Nordby et al 2006 ; Stisen et al 2006 ; Dandanell et al 2018 ; Shaw et al 2020 ). Abundance of fatty acid transport proteins membrane-associated fatty acid-binding protein (FABPpm) and carnitine palmitoyltransferase 1B (CPT1B) have been associated with PFO (Chrzanowski-Smith et al 2021 ). However, the relationship between PFO and abundance of fatty acid transport protein cluster of differentiation 36 (CD36) has not been assessed.…”

Sex differences in skeletal muscle revealed through fiber type, capillarity, and transcriptomics profiling in mice

“…In females, there tends to be lower exercise‐associated muscle fatigue (Billaut and Bishop, 2012 ; Fulco et al, 1999 ; Hakkinen, 1994 ; Wiecek et al, 2016 ), a higher prevalence of “oxidative” fibers (e.g., type I, type IIa) and lower prevalence of “glycolytic” fibers (type IIx, type IIb) (Miller et al, 1993 ; Staron et al, 2000 ). Peak fat oxidation during graded aerobic exercise (expressed per fat‐free mass) is significantly higher in females when matched to males of similar body composition (see: (Chrzanowski‐Smith et al, 2021 ; Devries, 2016 ) and references therein). Nevertheless, sex differences in some muscle phenotypes appear to be context‐dependent.…”

Exercise Fat Oxidation Is Positively Associated with Body Fatness in Men with Obesity: Defying the Metabolic Flexibility Paradigm

“…Further studies need to analyze whether body fat percentage is associated with circulating free fatty acids levels, muscular fatty acid uptake, mitochondrial fatty acid transport and intramuscular triglyceride hydrolysis and oxidation. In addition, future studies should determine whether Metflex and body fat percentage are related with the genotype of the ADRB3, CD36 and ACE genes and the muscle content of CPT and ATGL which have been associated with MFO [ 42 , 43 , 44 , 45 ].…”