Skeletal muscle and heart LKB1 deficiency causes decreased voluntary running and reduced muscle mitochondrial marker enzyme expression in mice

Abstract

Thomson DM, Porter BB, Tall JH, Kim H-J, Barrow JR, Winder WW. Skeletal muscle and heart LKB1 deficiency causes decreased voluntary running and reduced muscle mitochondrial marker enzyme expression in mice. Am J Physiol Endocrinol Metab 292: E196 -E202, 2007. First published August 22, 2006; doi:10.1152/ajpendo.00366.2006.-LKB1 has been identified as a component of the major upstream kinase of AMP-activated protein kinase (AMPK) in skeletal muscle. To investigate the roles of LKB1 in skeletal muscle, we used muscle-specific LKB1 knockout (MLKB1KO) mice that exhibit low expression of LKB1 in heart and skeletal muscle, but not in other tissues. The importance of LKB1 in muscle physiology was demonstrated by the observation that electrical stimulation of the muscle in situ increased AMPK phosphorylation and activity in the wild-type (WT) but not in the muscle-specific LKB1KO mice. Likewise, phosphorylation of acetyl-CoA carboxylase (ACC) was markedly attenuated in the KO mice. The LKB1KO mice had difficulty running on the treadmill and exhibited marked reduction in distance run in voluntary running wheels over a 3-wk period (5.9 Ϯ 0.9 km/day for WT vs. 1.7 Ϯ 0.7 km/day for MLKB1KO mice). The MLKB1KO mice anesthetized at rest exhibited significantly decreased phospho-AMPK and phospho-ACC compared with WT mice. KO mice exhibited lower levels of mitochondrial protein expression in the red and white regions of the quadriceps. These observations, along with previous observations from other laboratories, clearly demonstrate that LKB1 is the major upstream kinase in skeletal muscle and that it is essential for maintaining mitochondrial marker proteins in skeletal muscle. These data provide evidence for a critical role of LKB1 in muscle physiology, one of which is maintaining basal levels of mitochondrial oxidative enzymes. Capacity for voluntary running is compromised with muscle and heart LKB1 deficiency. adenosine 3Ј-cyclic monophosphate-activated protein kinase; muscle specific LKB1 knockout mouse; muscle mitochondria; citrate synthase AMP-ACTIVATED PROTEIN KINASE (AMPK) is a major regulator of skeletal muscle energy metabolism (3,5,27,29). It is activated in response to exercise and muscle contraction and other conditions of metabolic stress when AMP concentration increases (12,19,26,30). When active, AMPK works to restore cellular energy balance by promoting ATP-generating processes such as fatty acid oxidation and glucose uptake, while inhibiting anabolic processes, such as protein synthesis, that consume ATP (3-5, 14, 27-29). In addition to its role in maintaining energy homeostasis during exercise, AMPK is also thought to play an important role in many adaptations to chronic exercise such as elevations in protein levels of GLUT4, hexokinase II, and mitochondrial proteins (2,7,9,25,31,34). AMPK is a heterotrimer composed of a catalytic ␣-subunit and regulatory ␤-and ␥-subunits. Binding of AMP to the ␥-subunit of AMPK promotes phosphorylation at Thr 172 on its ␣-subunit, which is requisite for its activity. Several...

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

“…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.…”

FGF21 ameliorates diabetic cardiomyopathy by activating the AMPK-paraoxonase 1 signaling axis in mice

“…AMPK acts as a metabolic master switch regulating several intracellular systems including the cellular uptake of glucose, the β-oxidation of fatty acids, and the biogenesis of glucose transporter 4 and mitochondria [44,45]. The energy-sensing capability of AMPK can be attributed to its ability to detect and react to fluctuations in the AMP:ATP ratio that take place during rest and exercise [45,46]. AMPK signaling pathways are activated by adipokines, including adiponectin and leptin secreted from adipose tissues, which play several distinct but important physiological and pathological roles in the body [47,48].…”

Role of 5′AMP-activated protein kinase in skeletal muscle

“…14 In situ electrical stimulation-induced AMPK phosphorylation/activity is abolished to a large extent in the absence of LKB1, and thus, at least under these conditions, LKB1 seems to be the principal AMPK regulator in mouse skeletal muscle. 15,16 In skeletal muscle, AMPK is activated by acute exercise in both rodents and humans in an exercise intensity-dependent manner. Exercise at 60-75% of VO 2peak appears to be necessary for AMPK activation in humans (for references see Wojtaszewski et al 17 ) and at these intensities complexes containing a2-AMPK are regulated to a greater extent than complexes containing a1-AMPK.…”

“…45 Yet in support of a role for AMPK signalling in expression of mitochondrial proteins, we have found that basal expression of a number of mitochondrial proteins was significantly reduced in nontrained a2-AMPK KO mice 45 and recently similar observations were reported in the LKB1 KO mouse. 15 Thus, it is likely that the disturbed energy balance observed during acute exercise in the a2-AMPK KO (and likely also in the LKB1 KO mouse) partly results from decreased ability to generate ATP.…”