AMP-activated protein kinase (AMPK) plays an important role in controlling energy homeostasis and is envisioned as a promising target to treat metabolic disorders. In the heart, AMPK is involved in short-term regulation and in transcriptional control of proteins involved in energy metabolism. Here, we investigated whether deletion of AMPK␣2, the main cardiac catalytic isoform, alters mitochondrial function and biogenesis. Body weight, heart weight, and AMPK␣1 expression were similar in control littermate and AMPK␣2 ؊/؊ mice. Despite normal oxygen consumption in perfused hearts, maximal oxidative capacity, measured using saponin permeabilized cardiac fibers, was ϳ30% lower in AMPK␣2 ؊/؊ mice with octanoate, pyruvate, or glutamate plus malate but not with succinate as substrates, showing an impairment at complex I of the respiratory chain. This effect was associated with a 25% decrease in mitochondrial cardiolipin content, the main mitochondrial membrane phospholipid that is crucial for complex I activity, and with a 13% decrease in mitochondrial content of linoleic acid, the main fatty acid of cardiolipins. The decrease in cardiolipin content could be explained by mRNA downregulation of rate-limiting enzymes of both cardiolipin synthesis (CTP:PA cytidylyltransferase) and remodeling (acyl-CoA:lysocardiolipin acyltransferase 1). These data reveal a new role for AMPK␣2 subunit in the regulation of cardiac muscle oxidative capacity via cardiolipin homeostasis. Diabetes 56: 786 -794, 2007
Sarcoplasmic reticulum (SR) calcium pump function requires a high local ATP/ADP ratio, which can be maintained by direct nucleotide channelling from mitochondria, and by SR-bound creatine kinase (CK)-catalysed phosphate-transfer from phosphocreatine. We hypothesized that SR calcium uptake supported by mitochondrial direct nucleotide channelling, but not bound CK, depends on the juxtaposition of these organelles. To test this, we studied a well-described model of cytoarchitectural disorganization, the muscle LIM protein (MLP)-null mouse heart. Subcellular organization was characterized using electron microscopy, and mitochondrial, SR and myofibrillar function were assessed in saponin-permeabilized fibres by measuring respiration rates and caffeine-induced tension transients. MLP-null hearts had fewer, less-tightly packed intermyofibrillar mitochondria, and more subsarcolemmal mitochondria. The apparent mitochondrial K m for ADP was significantly lower in the MLP-null heart than in control (175 ± 15 and 270 ± 33 μM, respectively), indicating greater ADP accessibility, although maximal respiration rate, mitochondrial content and total CK activity were unaltered. Active tension in the myofibres of MLP-null mice was 54% lower than in controls (39 ± 3 and 18 ± 1 mN mm −2 , respectively), consistent with cytoarchitectural disorganization. SR calcium loading in the myofibres of MLP-null mice was similar to that in control myofibres when energy support was provided via Bound CK, but ∼36% lower than controls when energy support was provided by mitochondrial (P < 0.05). Mitochondrial support for SR calcium uptake was also specifically decreased in the desmin-null heart, which is another model of cytoarchitectural perturbation. Thus, despite normal oxidative capacity, direct nucleotide channelling to the SR was impaired in MLP deficiency, concomitant with looser mitochondrial packing and increased nucleotide accessibility to this organelle. Changes in cytoarchitecture may therefore impair subcellular energy transfer and contribute to energetic and contractile dysfunction.
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