Oki doki, ik wil best toelichtten wat ik zeg hoor:
(vergeef me dat ik de plaatjes er niet tussenzet, als er behoefte aan is, dan wil ik ze er later nog wel in editen)
Science has made some decent progress in identifying what may and I stress, may, be occuring during skeletal muscle hypertrophy and it's causes. Even though there are gaps in the total process, the foundations appear to be rather solid. It is these foundations that I will briefly touch on over the next few pages.
Translation, Protein Synthesis and Hypertrophy
Increases in skeletal muscle mass are mediated via protein turnover, the balance between protein synthesis and protein breakdown also known as "protein accretion" (1).
There are many controls that govern changes in protein synthesis and eventual gain in muscle mass.
Incorporation of both transcriptional and translational inputs can influence the protein synthetic rate (2). Generally, alterations in protein synthesis associated with altered gene transcription generally occur over a period of days to weeks (3), whereas increased mRNA translation (i.e. the process of synthesizing a protein based on the information encoded by the mRNA) can be manifested within minutes to hours (4).
Transcription and translation each contain three distinct steps (initiation, elongation, termination) with the predominant influence belonging to the initiation phase (5,6). However, translation is different and unique because mRNA is summoned and recruited rather than produced and this process is responsive to acute mechanical, metabolic, nutritional alterations (7).
Translation initiation essentially revolves around two main components mediated by eukaryotic initiation factors (eIFs) that control protein synthesis rate-limiting events. The first of the two components allows the ribosome to bind to the mRNA (eIF4F complex), the second brings the ribosome to the site on the mRNA where translation begins (eIF2/eIF2B). An essential mechanism for regulating growth within translation initiation involves the mammalian ‘target of rapamycin’ (mTOR) protein. Two common downstream targets of mTOR are the 70-kDa ribosomal proteins S6 kinase (S6K1) and the eIF4E-binding protein-1 (4E-BP1)(8).
A common misconception regarding changes in translation initiation is that activation of any protein in this pathway corresponds with increases in protein synthesis. For our purposes, after resistance exercise, elevations in protein synthesis have shown to be delayed for several hours yet mTOR controlled events can be rapidly upregulated during this very same period (9). Later, increases in protein synthesis appear to coincide with eIF2B changes (10). It’s becoming indisputable that chronic mTOR signalling is very valuable for increasing cell size and therefore increased muscle mass as blocking this pathway almost completely blocks the response (11). The downstream mTOR target, S6K1, strongly linked with muscle hypertrophy (12), is also crucial.
Currently it is safe to propose that both components of translation initiation are essential to increased muscle mass. Events linked with eIF2B regulation appear to regulate the acute changes in protein synthesis following resistance exercise, whereas activation of mTOR/4E-BP1/S6K1 pathways appears to result in synthesis of proteins necessary to "enhance" the translational process, creating an optimal environment for increases in translational capacity and hence the capacity for protein synthesis with long-term training.
Chronic vs. Acute-Once is not enough
Recent studies designed to better understand the regulation of translation initiation show us that following an acute bout of resistance exercise distinct eIF proteins are rapidly phosphorylated (13). Intermittent and transient activation of these proteins may provide better control for the modulation of a growth response. Or simply, the responses appear to be temporal and the acute impact of resistance exercise on mRNA translation likely becomes cumulative with each successive bout performed; it therefore appears that this pathway is intermittently turned on with repetitive resistance exercise and distinct mRNAs (ribosomal proteins, etc.) may accumulate to a point where an increase in the amount of specific proteins occurs (14). These responses highlight the chronic and acute more rapid control mechanisms associated with transcription and translation, that contribute to achieving muscle hypertrophy (Fig. 2).
Figure 2
Contractions, Stretch and Strain-Negatives vs. Positives, how about both
Over time the world of body building has seen many routines come and go and all had their own dogma on how to perform the reps. Many have touted slow or fast reps, full or diminished range of motion, static or isotonic. But again there was some commonality in them all, strain. It has been shown that strain is a potent stimulator of hypertrophy (15).
What hasn’t been so pronounced is which mode of contraction produces the most hypertrophic response (16-20). The debate still rages as to whether eccentrics (negatives) are better, worse or the same as concentric (positives).
What can be seen is that the issue of contraction mode isn’t much of an issue at all. Most human in vivo movement uses both and resistance training is the same. We raise the weight, we lower the weight, we do it again. Lending the tissue to the extremes of both contraction modes. The extent of muscle fiber strain is dependant on the compliance of the series elastic elements that not only tie the muscle fibers to our bones but also hold the fibers in their respective place. These elastic series elements take a large amount of force before stretching to a point where the force is then transmitted to the fibers themselves. What this means to a person moving an object is; even when stretching the entire muscle tendon complex the degree of stretch needed before actual strain is felt on the fiber depends on many things but there is hope. Looking into the mechanics of muscle tendon units (21) it’s been seen that two things predominantly affect the level of fiber strain, the length of the muscle when the stretch shortening begins and the number of stretch shortening cycles themselves.
If a muscle is pre-stretched in vivo the series elastic elements are already stretched and become stiffened, allowing a greater amount of force to be directly applied to the fiber. Using the other means it’s apparent that repetitive stretch shortening cycles stiffen the series elastic elements as well, again allowing more force to be directly applied to the muscle fibers (22).
How this ties into translation is two fold.
Fiber strain acts on the Mechanotransduction (23) mechanisms within the cell itself. This is a term used which denotes the bodies ability to turn a mechanical signal into a chemical signal. When cells are stretched the stretch is picked up by a couple notable elements. One of these is the Focal Adhesion Complex (24). The FAC, as it’s known, are sites where the extracellular matrix is physically coupled to the cytoskeleton within the cell. In skeletal muscle FAC can be found at the myotendinous junctions, neuromuscular junctions and in structures that lie above the z-bands named costameres. The FAC are protein dense regions and most of the molecules in the FA contain multiple domains that can interact with a variety of molecular partners. One of the major constituents of the FA is the family of cell surface receptors termed integrins (24). As the cell wall is stretched these integrins then transmit the stretch to the cell nucleus, which in turn up-regulates or down-regulates translational mechanisms. Another stretch sensor is the Stretch Activated Channel (25) or SAC. As a cell is stretched these channels are opened allowing ion flow in or out of the cell, the increased flux of ions can then increase translation items relevant to protein synthesis, metabolism or other cellular functions.
Much of the work on translational events revolved around the autocrine and or paracrine release of growth factors. It is proposed that the PI3K/Akt-1 pathway and subsequent mTOR pathway was dependant on the growth factor input. However it’s been shown (26) that mechanical stimuli are indeed similar to growth factors in that they require signalling through both PI3K and mTOR to promote an increase in protein synthesis but, unlike growth factors, mechanical stimuli activate mTOR-dependent signalling events through a PI3K/Akt1-independent mechanism and the release of locally acting factors is not needed for the induction of this pathway. Since PI3K is indispensable for growth factor-based signalling through mTOR, it appears that mechanical stimuli and growth factors provide their own distinct inputs through which mTOR co-ordinates an increase in the translational upregulation and efficiency.
Amino Acids-The building blocks
Over the last 25 years numerous studies on protein metabolism involving oxidation, synthesis and breakdown have been performed (27). It’s is this body of evidence that makes it abundantly clear that amino acids are a critical component to building muscle mass. It’s also become convincingly clear that the exogenous amounts of available AA are critical to signalling chains (28). Of the EAA’s made available through the infusion or oral dosing studies, the importance of the Branch Chain Amino Acid Leucine is coming to the forefront (29-31). Not so much in its role during energy expenditure but because of it’s prominence in signalling anabolic translational events leading to increased protein synthesis (32).
Leucine’s effect on protein synthesis is controlled through upregulation of the initiation of mRNA translation. As in the case of mechanical stimulation a number of differing mechanisms, including phosphorylation of ribosomal protein S6K, eIF4E BP1, and eIF4G, contribute to the effect of leucine on translation initiation. These mechanisms not only promote global translation of mRNA but also contribute to processes that mediate the selection of mRNA for translation. MTOR again is a key component in a signaling pathway controlling these phosphorylation-induced mechanisms. The activity of mTOR toward downstream targets is controlled in part through its interaction with the regulatory-associated protein of mTOR (known as raptor) and the G protein b-subunit-like protein. Upstream members of the pathway such as Rheb, a GTPase that activates mTOR, and TSC1 and 2, also known as hamartin and tuberin respectively, also control signaling through mTOR.
Inhibitory Signalling
With the advent of newer research putting light on the known mTOR/S6 chain it is becoming more and more clear that the AKT/mTOR/EIF4 chain is a very important regulatory mechanism in muscle growth (33). As with all signal chains in the human body there are signals that also combat the actions. Hypertrophy and increased protein synthesis via increased translation is no different.
The Switch
It has been noted by many researchers that protein synthesis does not occur for several hours after the exercise is completed (34-36). Recent work (37) has identified one possible mechanism that can be the cause. Called the “AMPK-AKT” switch (37), this switching of translational events leading to protein synthesis can be seen during the difference in exercise mode. Long duration endurance type activity causes increased activity in AMPK (5'AMP-activated protein kinase) this kinase then turns on events that switches off events that use ATP for anything other than fuel replenishment inside the cell, including the mTOR activated protein synthesis chain.
AMPK is another member of the heterotrimeric serine/threonine protein kinase. AMPK is composed of a catalytic alpha subunit and non-catalytic beta and gamma subunits (38, 39). The mammalian genome contains seven AMPK genes encoding two alpha, two beta, and three gamma isoforms. AMPK signaling is elicited by cellular stresses that deplete ATP (and consequently elevate AMP), the AMP/ATP ratio, by either inhibiting ATP or accelerating ATP consumption. Although AMP is produced in several cellular reactions, it most importantly appears to be the adenylate kinase reaction: 2ADP <> ATP + AMP. In healthy, resting muscle the ATP:ADP ratio is maintained at a high level, and therefore AMP is very low. However, if the cell experiences a stress that depletes ATP, the ATP:ADP ratio will fall (analogous to the battery becoming discharged), and a large increase in AMP will follow. These are exactly the conditions in which AMPK is activated.
Treatments that activate AMPK can either be stresses that interfere with ATP production, such as heat shock, metabolic poisons, glucose deprivation, hypoxia, or ischaemia (40,41) or stresses that increase ATP consumption, such as exercise in skeletal muscle (42). These findings led to the concept that the AMPK system acted as a “fuel gauge” or “cellular energy sensor” (41). This concept was reinforced by findings that AMPK was allosterically inhibited by physiologically adequate concentrations of phosphocreatine (43).
It has been shown that AMPK is a central mediator of insulin-independent glucose transport, which enables fuel-depleted muscle cells to take up glucose for ATP regeneration under conditions of metabolic stress (40). When rat epitrochlearis muscles were isolated and incubated in vitro under conditions that evoke metabolic stress accompanied by intracellular fuel depletion, rates of glucose transport in the isolated muscles were increased by all of these conditions, contraction (5-fold above basal), hypoxia (8-fold), and hyperosmolarity (8-fold) Fig. 3. All of these simultaneously increased both isoforms of AMPK, alpha1 and 2. There was close correlation between alpha1 and alpha2 AMPK activities and the rate of glucose transport, irrespective of the metabolic stress used, all of which compromised muscle fuel status as judged by ATP, phosphocreatine, and glycogen content.
Fig. 3 The fold increase in AMPK during differing metabolic stress
Fatigue-The TUT party crasher
During contractions, whether sustained static or repeated dynamic a big influence over the duration or number of contractions performed is fatigue. The overall cause of fatigue is still being debated as its effects on contraction are so pronounced in varying systems and no single consensus has been defined.
Muscle contraction increases muscle metabolism by an order of magnitude (44), this magnitude is influenced by type, intensity, duration and frequency of contraction and the fatigue rate in muscle falls in line with this magnitude. It has long been realized that the metabolic cost of muscle activation is a primary factor in fatigue (45), not necessarily the only factor but the buildup of metabolic byproducts (46-48) and depletion of substrate (49) have a large part to play. The results of many metabolic studies do not demonstrate, with any consistency, that it’s a matter of only one metabolite being the cause of fatigue, but they do show that several substances can alter force generation under varying conditions (50-52). In further support of a metabolic basis for fatigue, several studies have demonstrated that during short-duration, high-intensity exercise (both voluntary contraction and electrically evoked contraction), protocols that produce the greatest metabolic change also produce the greatest fatigue (53-57), although other factors, such as activation failure, are likely to be involved in the decline in force (58), but this factor goes far beyond the scope and intent of this brief.
The metabolic demand of muscle contraction is associated with the ATP hydrolysis occurring at three ATPases: 1) the sodium/potassium (Na+/K+) ATPase associated with maintaining the resting membrane potential of the sarcolemma, 2) the actin myosin (AM) ATPase associated with cross-bridge cycling and force production, and 3) the sarcoplasmic reticulum (SR) Ca2+ ATPase associated with Ca2+ reuptake at the SR.
The demand of the AM-ATPase is related to the force produced by a muscle (59), as ATP consumption increases proportionately with force during voluntary contractions. ATPase activity, however, is lower in fibers that have been chemically skinned to remove the SR, this eliminates the metabolic demand associated with the SR Ca2+ ATPase. This coincides with findings suggesting that between 20 and 40% of the ATP hydrolysis that occurs with muscle contraction is thought to result from noncontractile (i.e., non AM ATPase) ATPase activity (60). This indicates that with repeated contractions the ATP used for all three ATPases would be higher than what is seen during isometric exercises. The increased ATPase activity indicates that during repetitive contractions AMPK activity would also be higher especially if the AMP/ATP ratio is severely affected.
Now that we’ve reviewed how the metabolic fatigue induced during repetitive contractions can cause a diminished response through the AMPK-AKT switching event, lets look into how the lactic acid burn and the pump can also affect it through increased acidosis, hypoxia and hyperosmolarity.
Let's move on and look at what inhibitors alter this process.
Blood Flow and it’s Effects
Adequate perfusion, blood flow across the tissue bed, is vital to the health and proper functioning of skeletal muscle. In healthy tissue, the metabolic demands of the muscle will largely determine the degree of its perfusion. While blood flow through the arteries is important in determining how much blood can reach the muscle, the amount of blood that enters the muscle bed via the micro-vasculature will determine the degree of gas and nutrient exchange, profoundly impacting the contractile state of the tissue.
Blood flow during resistance exercise highly oscillates due to the high intra-muscular pressures that are generated during contractions. High intra-muscular pressures impede (occlude) muscle blood flow, with the result that blood flow approaches zero during contractions but is greatly elevated after contractions (62,63).
The extent of temporary occlusion is directly proportional to the intensity of contraction and this continues to about 60% MVC (64). At this point the muscle blood flow becomes completely occluded and remains occluded for the duration of the contraction phase regardless of any further increases of force (65,66).
The ischaemia that occurs during the occluded state causes an increase in non-oxidative metabolism via hypoxia a.k.a. ischeamic hypoxia (67). Hypoxia is a condition of lessened oxygenation. The reduced blood flow during ischaemia does not allow the blood to circulate and therefore it does not re-oxygenate.
Interestingly this is true also when contraction frequency is increased, or the contractions retain sufficient tension for a prolonged period. The expansion of the muscle blood volume, as contraction frequency increases, is a result of the muscle vascular bed being expanded by vasodilator processes that occur with an increased metabolic rate, and occurs even though the time between contractions (“filling” time) is decreased (68). One of the more interesting observations seen is that the volume of blood contained in the muscle is greater during these states. A greater volume of blood contained in the muscle allows for a greater ejection of blood for a given contraction during the relaxation phase. In the case of prolonged tension or insufficient relaxation times the pooling that occurs interferes with nutrient and gas exchange.
All of these blood flow responses to contraction have an impact on the internal environment and metabolic state of the muscle. Every time ATP is broken down to form ADP and Pi, a proton is released. When the ATP demand of muscle contraction is met by mitochondrial respiration, IE oxidative metabolism, there is no proton accumulation in the cell, as protons are used by the mitochondria for oxidative phosphorylation. When the exercise intensity increases beyond steady state or there is a reduction in oxygen availability that there is a need for greater reliance on ATP regeneration from glycolysis and the phosphagen system (69). The ATP that is supplied from these non-mitochondrial sources is eventually used to fuel muscle contraction, which increases proton release and causes the acidosis that accompanies intense exercise. Lactate production increases under these cellular conditions to prevent Pyruvate accumulation and supply the NAD + needed for the second phase of glycolysis. Thus increased lactate production coincides with cellular acidosis.
Secondarily to the energetic effects are the cross sectional area changes that occur within the cell itself. The shifting of water and pooling of blood is what is commonly referred too as the “pumped” look. Increased perfusion directly increases muscle CSA. Edema, water shifting caused by hyperosmolarity and fluid pressures can also cause this temporary increase (70-72).
The human body is composed of 50-60% water, which corresponds to ~70% of lean body mass being water. Skeletal muscle amounts to ~40% of body weight, of which in the resting state 75% is water, accounting for around one-half the body water. The distribution of total muscle water in muscle at rest is ~90% cellular, ~9% in interstitial spaces, and ~1% in plasma.
The fluid distribution volumes are substantially changed during muscular activity. During exercise, there is an acute uptakeof fluid by the active muscle cells; hyperosmolarity is one mechanism that explains this shift.
Some of the osmolytes that may be responsible for this are lactate, potassium, sodium and chloride (73). Another osmolyte that appears to have a profound effect on cellular volume is CrP (Creatinephosphate) (74). During exercise CrP is broken down to 1 mol of Creatine and 1 mol of inorganic Phosphate, the new steady state level effect on osmolality of this breakdown may be considerable causing increased water shifting to occur (75).
Now that we have gone through several mechanisms that can contribute to the inhibitory signalling during resistance training let’s begin to peace it together and knit a plan of action to counter or at least diminish the effect.
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