Mitochondrial and performance adaptations to exercise training in mice lacking skeletal muscle LKB1

Abstract

and its downstream targets of the AMP-activated protein kinase family are important regulators of many aspects of skeletal muscle cell function, including control of mitochondrial content and capillarity. LKB1 deficiency in skeletal and cardiac muscle (mLKB1-KO) greatly impairs exercise capacity. However, cardiac dysfunction in that genetic model prevents a clear assessment of the role of skeletal muscle LKB1 in the observed effects. Our purposes here were to determine whether skeletal musclespecific knockout of LKB1 (skmLKB1-KO) decreases exercise capacity and mitochondrial protein content, impairs accretion of mitochondrial proteins after exercise training, and attenuates improvement in running performance after exercise training. We found that treadmill and voluntary wheel running capacity was reduced in skmLKB1-KO vs. control (CON) mice. Citrate synthase activity, succinate dehydrogenase activity, and pyruvate dehydrogenase kinase content were lower in KO vs. CON muscles. Three weeks of treadmill training resulted in significantly increased treadmill running performance in both CON and skmLKB1-KO mice. Citrate synthase activity increased significantly with training in both genotypes, but protein content and activity for components of the mitochondrial electron transport chain increased only in CON mice. Capillarity and VEGF protein was lower in skmLKB1-KO vs. CON muscles, but VEGF increased with training only in skmLKB1-KO. Three hours after an acute bout of muscle contractions, PGC-1␣, cytochrome c, and VEGF gene expression all increased in CON but not skmLKB1-KO muscles. Our findings indicate that skeletal muscle LKB1 is required for accretion of some mitochondrial proteins but not for early exercise capacity improvements with exercise training. liver kinase B1; adenosine 5=-monophosphate-activated prokine kinase; mitochondria; exercise training; skeletal muscle EXERCISE TRAINING RESULTS IN A HOST OF ADAPTATIONS in skeletal muscle that contribute to an enhanced capacity for subsequent exercise performance. Among the most significant of these is an increase in mitochondrial content and enzyme activity (14). Although the mechanisms involved in mitochondrial biogenesis are not fully defined, existing evidence suggests that AMPactivated protein kinase (AMPK) plays an important role in promoting this process (1, 51). AMPK is potently activated under conditions of low cellular energy, when ATP levels decline and AMP/ADP levels rise (4, 52). In skeletal muscle, this occurs during exercise or muscle work (50). Upon activation, AMPK generally signals the allocation of cellular resources to catabolism and energy production while reducing growth and proliferation signals. In line with these broad functions, chronic activation of AMPK, using the AMP mimetic AICAR, increases mitochondrial enzyme protein content and activity (18,51). This is likely due, at least in part, to increased peroxisome proliferator-activated receptor-␥ coactivator 1␣ (PGC-1␣) content (18, 27) and phosphorylationmediated PGC-1␣-dependent transcr...

AMPKα is essential for acute exercise-induced gene responses but not for exercise training-induced adaptations in mouse skeletal muscle

“…However, in AMPK␣2 KD mice, exercise results in higher VEGF mRNA levels than in WT mice (66). On the contrary, the increase seen in VEGF mRNA of WT mice with electrical stimulation is fully ablated in muscle of skmLKB1 KO mice (52). Again, the present results using the AMPK␣ mdKO mouse model in which both catalytic subunits of AMPK are ablated show that AMPK␣ is indeed required for exercise-induced increases in skeletal muscle VEGF mRNA.…”

“…Thus, although the majority of studies suggest that altered AMPK signaling plays a role in basal CS activity, it is clearly not the sole determinant. Habitual locomotor activity seems not to be an explanatory factor either in that it is normal in AMPK/LKB1-deficient mouse models that at the same time show either unaltered (13) or decreased (48,52) levels of basal CS activity.…”

“…The normal basal activity of CS in AMPK␣ mdKO compared with WT mice is in agreement with our previous data in these mice (29) and previous data from AMPK␣2 KD mice (1). However, a decreased basal CS activity has been found in AMPK␣2 KO (25), AMPK␣2iTG (51), AMPK␤1␤2M-KO (48), LKB1 MKO (24,54), and skmLKB1-KO mice (52). Thus, although the majority of studies suggest that altered AMPK signaling plays a role in basal CS activity, it is clearly not the sole determinant.…”

“…A heightened contraction-induced activity of AMPK␣1 in AMPK␣2 knockout (KO) mouse muscle could suggest that AMPK␣1 may compensate for the lack of AMPK␣2 to induce normal mRNA and protein responses (26). Supporting this, mice lacking LKB1 (serine/ threonine kinase 11) in skeletal muscle seem less capable of adapting to acute exercise and exercise training (52). Thus, a more complete ablation of AMPK activity, either by deleting the primary upstream kinase LKB1 or by disrupting both ␤-isoforms, appears to effectively inhibit muscle adaptations to contractile activity.…”

New strategies in sport nutrition to increase exercise performance

“…AMPK also plays a key role in controlling running capacity and certain adaptive processes in response to endurance exercise training [25,26]. In a feed forward fashion AMPK can translocate to the nucleus [24,27] where it regulates Histone de-aceytlases, transcription factors and transcriptional co-activators such as histone deacetylase 5 (HDAC5), myocyte enhancing factor 2 (MEF2) and peroxisome proliferator activated receptor-γ co-activator-1α (PGC-1α) respectively (Figure 1) [28][29][30].…”