Is Your Body Too Efficient?

Efficiency is on everyone’s minds these days.

People are trading in their gas guzzling Hummers for energy efficient hybrids.

They’re buying energy efficient fridges, stoves and toasters.

They’re replacing their regular light bulbs with energy efficient compact fluorescent light bulbs.

Why? Because energy efficient is good all around, right? It’s good for you because it costs less, and good for the environment because you use less energy.

People are also trying to be more efficient in their personal and professional lives.

“Getting things done” is a mantra of the busy worker, and entire stores simply sell boxes and closet organizers so that we can be more efficient in alphabetizing our shoes and trying to store the Xmas lights in something other than a gnarly tangled ball.

In general everybody is gung ho for any type of efficiency. You never hear, “I’m trying to be as inefficient as possible this year.” Nope. It’s all about efficiency… until you start talking about losing weight.

Is your body too efficient?

When people say that they have a “slow metabolism”, what does that mean?

Assuming that these people actually have a slow metabolism — instead of “slow metabolism” being a convenient euphemism for “overeating and under-exercising” — it means their bodies are too efficient. Compared to the average person, their bodies are either better at getting energy from the food they eat, or they’re really stingy in using energy.

All you out there with “slow metabolisms”, think of yourselves as the energy efficient model, while those people who can eat whatever they want are the gas guzzling model.

Building an inefficient muscle

In the study I’m reviewing this week, the researchers make a genetically modified mouse that has a mutated muscle “gas gauge”, if you will, that makes the mouse’s muscle inefficient.

Normally, a muscle is very good at knowing how much energy it has left. When stores are low, it’ll limit how much energy it uses. From an evolutionary perspective, especially when food was scarce, this type of efficiency was really important for survival.

Your muscle’s batteries

Before I tell you about the exact mutation in the mouse, I need to tell you about the muscle’s batteries.

When I talk about muscle energy, most of you probably think about carbohydrates (glycogen), sugars (glucose), fats, and even proteins, but that’s not the energy a muscle cell or any cell is most interested in. They’re interested in ATP [1].

ATP (or adenosine triphosphate) is a molecule that cells use to store energy, kinda like batteries. In muscle the three main users of all energy are called ATPases (proteins that breakdown and use ATP)*[2]:

Na⁺/K⁺ (sodium potassium) ATPase
Ca²⁺ (calcium) ATPase
Myosin-ATPase

*Note: ATPase is pronounced A-T-P-aze not A-T-passé

In an upcoming review I’ll go into more detail about what these ATPases do, and how they affect your muscle.

The energy controlling protein

Since ATP is so important to muscle (in fact any cell) your body has a few ways of detecting how much is left. Today, we’re going to look at the ATP-sensitive K⁺ channel,  or K_ATP channel for short[3-4].

I’m sure you’re asking, “What the heck is a channel? Is this like the English Channel? Or a TeeVee channel?”

A channel is a protein passageway for a specific molecule; in this case the passage is for potassium (K⁺).

Imagine a strainer that has holes (obviously). It lets water pass with no problem, but not the broccoli you were soaking. In the cell, the potassium is the water, and everything else is the broccoli. The broccoli can’t pass through the channels, so it stays in the cell.

Less ATP means the channel opens more, letting more potassium out, which shortens the activation of the muscle (by shortening the action potential). Basically, this channel detects that there is less energy (ATP) in the cell and then prevents the muscle cell from contracting fully.

What does this have to do with you (or with mice)? Well, without further ado I give you this week’s article.

Alekseev AE, et al. Sarcolemmal ATP-sensitive K(+) channels control energy expenditure determining body weight. Cell Metab. 2010 Jan;11(1):58-69.

Methods

The researchers actually made two types of mutant mice, both with the gene that makes the K_ATP channels (KCNJ11) mutated so that the K_ATP channels won’t work.

The first mutant mouse had the KCNJ11 gene mutated in every cell of the body, so that no K_ATP channels throughout the mouse’s entire body worked. I’ll call these mice “mutant mice” from now on.

The second mutant only had the KCNJ11 gene mutated in the skeletal muscle cells. Thus, only muscle cells had nonworking K_ATP channels. The rest of the body worked normally. I’ll call this mutant “muscle mutant.”

By the way, I say “skeletal muscle” specifically because there are other muscles like cardiac muscle (heart) or smooth muscle (i.e. intestine, arteries).

Warning: Molecular Biology Ahead

For those interested in making a skeletal muscle-specific mutant, the researchers used a muscle-specific promoter (MyoD promoter).

A promoter is DNA that is next to a specific gene, which in the right environment triggers the making of the protein from the gene[5]. In muscle, muscle-specific promoters are only active in muscle, so that you can have liver cells and muscle with the same DNA making different proteins and doing different things.

Comparing the mice

Once the mice were made (yes I realize that probably sounds a wee bit strange) the researchers compared normal mice and mutant mice. They compared mice by:

Interestingly, the researchers also compared how big the fat cells were in the normal mice compared to the muscle mutants. Umkay, the mutation was in the muscle… but the researchers were comparing fat cells? Read on to find out why.

Results

As the mice aged, the mutation-related differences became obvious. By 5 months old the mutant mice had less body weight and by 12 months old the mutant mice had way less body fat (30% less fat under the skin or subcutaneous fat).

Now where it gets really interesting is that the mutant mice were just as active as the normal mice. They also ate more, but used more energy. By getting rid of the K_ATP channel, the mouse used more energy for the same amount of activity.

Then the researchers wanted to know what happened on a high fat diet. The mutant mice didn’t gain as much weight as the normal mice on a high fat diet.

Sounds great! The mutant mice were less energy efficient, they had less body fat, could eat more, and not gain as much weight compared to the normal mice. You’d think there has to be a downside to all this… and you’d be right.

Energy inefficiency and exercise

Reduced energy efficiency might have worked all right when the mice were just lounging around, but when they exercised, the mutant mice couldn’t really keep up to the normal mice.

Exercise involved running on a treadmill (starting at 2 mW and going to 30 mW for max oxygen capacity VO_2max ) or on a running wheel in their cage, but sorry, no weight training. During treadmill running, the mutant mice had more blood lactate build-up and in their cage they didn’t run as often, as long, or as far on their running wheel. All in all, the mutant mice weren’t too keen on exercise.

Muscle mutant fat cells

Fat cells in the muscle mutant were smaller than the normal mouse. Why? How can a mutation in muscle change fat cells?

The answer is that the mutant muscle is inefficient. It uses more energy. That energy comes from fat, and that fat would be found in fat cells, making them smaller. Hmm… sounds a bit like what happens with people with a fast metabolism.

Results

Mutant (for the KCNJ11 gene) mice without energy sensing protein (ATP-sensitive K⁺ channel) have less body weight and less body fat compared to normal lab mice.

Mutant mice gained less weight on a high fat diet compared to normal lab mice.

Mutant mice weren’t as active and didn’t do as well in endurance testing compared to normal mice.

Less body fat in mutant mice is from inefficiency by skeletal muscle that makes a greater energy demand.

Bottom Line

Getting rid of or reducing energy level sensing protein (ATP-sensitive K⁺ channel) may be a new anti-obesity treatment, though at the expense of any sort of aerobic capacity (endurance). Your muscle becomes less efficient so they use more energy all the time, making you warmer and thinner.

References

1. Lodish, Harvey; Berk, Arnold; Zipursky, S. Lawrence; Matsudaira, Paul; Baltimore, David; Darnell, James E. Molecular Cell Biology Section 2.4 New York: W. H. Freeman & Co.; 1999.
2. McComas AJ. Skeletal Muscle: Form and Function. page 215. Champaign, IL: Human Kinetics. 1996.
3. Matar W, Nosek TM, Wong D, Renaud J. Pinacidil suppresses contractility and preserves energy but glibenclamide has no effect during muscle fatigue. Am J Physiol Cell Physiol. 2000 Feb;278(2):C404-16
4. Bushman JD, Gay JW, Tewson P, Stanley CA, Shyng SL. Characterization and functional restoration of a potassium channel Kir6.2 pore mutation identified in congenital hyperinsulinism. J Biol Chem. 2009 Dec 23. [Epub ahead of print]
5. Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. Molecular Biology of the Cell Chapter 7. New York and London: Garland Science; 2002.