Muscle physiology – beyond the basics II

??????????? In this iteration of the newsletter, I’ll continue discussing some elements of skeletal muscle physiology, specifically those related to metabolism or its support, that need to be updated in our teaching. I’ll follow a logical progression from circulatory supply and O2 transport to the intracellular transitions between aerobic and anaerobic metabolism. As always, the goal here is to inform and improve the education of students heading into physiology-based careers where accurate and complete descriptions are essential to their ability to reason effectively.

The first bit of historical inertia is related to the support of skeletal muscle (or any other tissue) metabolism through regulation of blood flow. Given recent studies utilizing more advanced techniques, August Krogh, the physiology pioneer and Nobel prize winner, has been shown to have been somewhat incorrect in his classic model for capillary blood flow. Krogh proposed that muscle capillaries are generally binary (either open or closed) and that increases in O2 delivery to working tissues occurs through recruitment of unperfused capillaries, each representing a relatively fixed unit of diffusive potential, effectively increasing the total vessel surface area over which diffusion is occurring. In reality, capillaries are not simply “on” or “off”, but rather experience gradations of perfusion based upon tightly regulated resistance of their arteriolar supply. At exercise onset, red blood cell (RBC) velocity and flux increase and raise the effectiveness of capillaries providing for O2?delivery. This supports current O2?delivery paradigms and experimental data suggesting that the primary determinant of O2?diffusivity from blood to interstitium is actually the number of RBCs in the capillary bed adjacent to the muscle fibers. As arterioles dilate, capillary hematocrit and O2 extraction rises significantly in a process referred to as longitudinal capillary recruitment. In this process, the anatomical capillary surface area available for diffusion does not increase, however it does become more effective due to a greater concentration of RBCs passing in close proximity to the working cells. A useful way of explaining this to students would be to ask them to consider vascular perfusion changes that occur with exercise as literally enhancing the collective surface area of RBCs contributing to O2 delivery as these cells pass through a local capillary bed.

It's also relevant to point out that regulation of arteriolar vasoactivity to adjust capillary bed flow rates and hematocrit occurs nearly instantaneously upon onset of exercise (<1 second) – a response too quick to result primarily from the relatively slow diffusion of muscle metabolites. While not fully understood, mechanisms initiating this rapid increase of muscle blood flow at exercise onset may be very different from those sustaining its steady state. Studies support a model wherein contraction-induced vascular deformation induces an almost immediate vasodilation possibly involving mechanosensitive ion channels. Regardless of the specific mechanism(s) responsible, this increased flow is certainly adaptive, as cellular supplies of ATP and creatine phosphate last only seconds. That makes enhanced O2 delivery essential to the avoidance of large increases in anaerobic metabolism and subsequent acidosis.

The next step in the progression would be to enhance O2 diffusion within the skeletal muscle cells themselves – or so one would think (more below). This is understood to be aided by the presence of intracellular myoglobin, especially in those cells adapted to remain aerobic (Type 1 – slow oxidative). First, let’s dispel with the myth that myoglobin functions as an O2 “storage” molecule. Unless you are teaching diving marine mammal physiology, this is simply a phrase that should be removed from the instructional verbiage regarding myoglobin. At the levels expressed in (non-diving) striated muscle, myoglobin is estimated to bind just enough O2 to supply aerobic metabolism at maximal exertion for less than a second! Obviously, storage is not myoglobin’s role in most cases. The problem is, there seems to be quite an array of current theories on the importance of this O2-binding pigment. Theoretically, the presence of myoglobin, a mobile intracellular binding agent, could increase the net rate of O2 diffusion (see previous article on diffusion) as long as binding and release kinetics are not limiting. Recent studies, however, indicate that the movement of intracellular myoglobin is limited due to its size and the tortuosity of the pathway created by cytoskeletal and other proteins. Nonetheless, subsarcolemmal mitochondria are surrounded by cytoplasmic myoglobin that is O2-saturated in muscle at rest. This oxymyoglobin “layer” desaturates during exercise, increasing O2-diffusing capacity (i.e., increasing the concentration gradient across the sarcolemma). In support of this notion, despite capillary PO2 falling during exercise due to enhanced extraction, a more precipitous decline occurs intracellularly from rest to active states (PO2 falls to ~2-5 mmHg @ 60-100% of VO2max) suggesting an elevated gradient driving transmembrane diffusion. What gets really interesting is that once muscle is active, and subsarcolemmal myoglobin is desaturated, intramyocyte (cytoplasmic) PO2 gradients are thought to be miniscule. This would seem to indicate a very low resistance pathway or some other support system for the enormous increase in myofiber ATP production and use (up to a 100-fold increase). The answer could rely on the next topic here – mitochondrial structure and function.

?Unless you are a muscle physiologist (perhaps even if you are), this one may blow your mind. When viewed three dimensionally, myocyte mitochondria are generally not “bean-like” in shape as we typically see them presented. In fact, the subsarcolemmal and intermyofibrillar mitochondrial populations aren’t truly distinct from each other. Rather, there is a system of mitochondrial connectivity, in essence, a mitochondrial “reticulum”, that may help explain the enhanced diffusivity of intracellular O2 and or “energy” dispersal in general! What I mean here is that most of us think of the electron transport chain as a collection of spatially grouped proteins that work together to generate a proton gradient that is immediately and locally tied to ATP synthesis. What if I were to tell you that subsarcolemmal (shallow) electron transport chains (ETCs) are undersupplied with ATP synthase but deeper (yet interconnected) intermyofibrillar ones are not? This would imply that O2 diffusing across the sarcolemma contacts ETCs that effectively use O2 and produce proton gradients (up through cytochrome IV), but which cannot extensively utilize that gradient to form ATP at complex V. Instead, the intramembranous space of the reticulum may be acting as an electrical charge conduit to the deeper ETCs. While this has yet to be systematically proven, the mitochondrial reticulum could be compensating for the relative slowness of intracellular O2 diffusion by providing a guiding pathway for the rapid transmission of proton flux both across and along the myocyte. This would provide for the production of ATP deep within the cell in the absence of equally significant O2 diffusion to this region. Whoa, right?

Lastly, let’s toss out some long-disproven fallacies regarding anaerobic metabolism and lactate production. Firstly, lactate is produced continuously, even at rest. It simply doesn’t accumulate due to consumption rates in oxidative pathways or recycling gluconeogenic reactions (Cori cycle) matching its production. This continues to be true in skeletal muscle, even at moderate activity levels, when anaerobically “geared” type II fibers produce and release lactate that is immediately consumed by adjacent type I fibers specializing in aerobic ATP production (see our textbook Figure below). While we might consider the free protons of lactic acid production to be a waste product when compensation mechanisms are exceeded, the lactate anion itself, instead, acts as a fuel. Lactate oxidation can actually exceed glucose flux at moderate levels of activity! Type I fibers use very little glucose/glycogen except when highly activated.

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This brings us to an assessment of what exactly is the trigger initiating a transition from aerobic to anaerobic ATP production. Classically (and incorrectly), this has been linked to an insufficient supply of O2 during strenuous exercise. In fact, it isn’t that O2 consumption exceeds its delivery that leads to O2 deficit … the deficit actually develops because O2 consumption isn’t high enough to match the time-dependent ATP demands of strenuous exercise. As intensity increases, the anaerobic use of stored glycogen increases due to metabolic demand of the muscle. Simply put, β-oxidation and mitochondrial metabolism of fats takes far longer than the production of ATP through glycolysis which can be much faster (up to 100-fold). Increased intensity also recruits fast twitch fiber types that are adapted exactly for this purpose – high “power” energy extraction (ATP/second) that is inherently low efficiency (ATP/calorie). This readily provides for the high muscular power output of this fiber type. Meanwhile, aerobic pathways that often dominate in slow twitch fibers are exactly the opposite – highly efficient at nutrient energy extraction but slow to do so (low energetic “power”). This of course matches up precisely with their slower myosin ATPase isoforms that inherently generate less muscular power.

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Wishing you a happy and healthy new year!

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