One of the recent themes of this blog has been rethinking the concept of damage being a bad thing.  The traditional view has been that we need to avoid damage, whether it is muscle, tendon, or some biochemical change at the microscopic level.  Recently, the paradigm has started to shift towards looking at damage not as some nasty consequence of training hard, but instead as the trigger that fuels adaptation.

In a series of articles in the Journal of Applied Physiology, this paradigm shift is being explored in regards to inflammation.  The traditional view on inflammation is that it is impairs recovery.  It’s the reason why trainers are reliant on ice for everything and that people pop NSAIDs like no other.  When in actuality, the picture is more complex and it seems like inflammation can play both sides of the coin and either impede or help repair depending on the amount and timing of it.  And changing the degree of inflammation via outside mechanisms can help or hinder adaptation.

What these 6 papers do is break down the myths and our current state of knowledge on the topic.  It’s a great glimpse into where exactly the research stands, what the unanswered questions are, and what the practical implications are.

Effects of prostaglandins and COX-inhibiting drugs on skeletal muscle adaptations to exercise Todd A. Trappe and Sophia Z. Liu

The first paper by Trappe and Liu looked at the influence of COX inhibiting drugs on exercise adaptation.  Trapper and Liu lay out the history of the research done, providing an interesting historical look at how our knowledge developed.  The basic theory is that when we exercise, a slew of prostaglandins are produced in response to the exercise and these may trigger downstream adaptations. The first hint of COX inhibitors having an effect on adaptation came in the 1990’s when studies started to find that taking acetaminophen or ibuprofen seemed to inhibit protein synthesis and prostaglandin increases following a large bout of eccentric exercise. Without going too far into it, this is what the authors found.

  • Substantial increases of prostaglandins in the muscle from resistance training and aerobic exercise.  During aerobic exercise, the amount is heavily influenced by the intensity.
  • Taking non-specific COX inhibiting drugs (Aspirin, ibuprofen, etc.) in normal prescribed amounts can significantly decrease prostaglandin amounts.
  • Cox-2 seems to be related more to injury stimuli and not exercise.
  • In older adults, taking NSAID’s
    chronically has generally shown increases in muscle strength and/or mass.
  • Acetaminophin (not generally a NSAID) actually inhibits prostaglandin synthesis.

So what is the take away?  Right now we have a situation where the acute research shows that taking a NSAID has an acute effect on protein synthesis and prostaglandin production.  One would assume that since these are the triggers for adaptation that it would harm long term adaptation.  What happens in the long term though is murkier.  The research has generally been on older adults who prevent a different problem than younger athletes.  In older adults, it appears that COX-inhibitors actually limits a trigger for muscle protein turnover.  Further complicating things is the fact that animal models show chronic long term interfearance between NSAIDs and muscle adaptations.

The bottom line is we know it changes the internal environment, we just don’t know if/what the long term effects on changing that environment are.

Does a NSAID a day keep satellite cells at bay? Abigail L. Mackey

In the second review, Dr. Mackey took things a step further and looked at whether NSAIDs had an effect on satellite cells in the muscle.  Satellite cells are essentially muscle stem cells that play a crucial role in repair and growth of a muscle.  As Dr. Mackey points out, they are triggered via “mechanical stimuli in the form or stretch or forceful contractions, damage to the muscle, pharmacological agents, and inflammatory conditions.”

Obviously if inflammation is a trigger, then it makes sense that taking away or dampening down inflammation may influence their activation.  According to Dr. Mackey, NSAIDs can either effect satellite cells via effecting growth factors or prostaglandins which both play a role in going from activation of a satellite cell to its fusion with myotubes of a muscle cell.

A summary of the findings:

  • studies infusing NSAIDs have blocked the satellite cell response to exercise.
  • Injestion of NSAID’s chronically appears to decrease the satellite cell response
  • It appears that timing matters, and that the triggers for satellite cell activation can be blunted within the hours prior to and just after exercise.
  • This may be due to NSAIDs dampening down of IGF-1 and growth factors (VEGF and bFGF)
  • Satellite cell content increases generally starts to be seen 24-48hrs after exercise and can  steadily increase for up to 8 days.
  • NSAIDs may have an effect on collagen synthesis and influence the connective tissue, although not enough studies have been done yet.
  • In animal studies, COX inhibitors blunt muscle hypertrophy.
  • One hypothesis for why NSAID effects differ in young vs. old people is the increase in systemic inflammation in older adults

What is the impact of inflammation on the critical interplay between mechanical signaling and biochemical changes in tendon matrix?

The next paper by Kjaer et al. looked at the effects of inflammation on tendon health.  In particular, they try to answer the question asked in the title.  The idea is similar to that of inflammations effect on muscular adaptations.  Research has shown that we get increases in prostaglandins in tendons just like in muscle.  So it follows that dampening this expression can have effects on factors such as collagen turnover and blood flow in the tendon.  Or in layman’s terms, that inflammation plays a role in tissue regeneration and repair.

The highlights include:

  • NSAID’s may decrease blood flow to the tendon by ~30%.
  • NSAID’s taken before exercise decrease prostaglandin concentration in the tendon for up to 3 days, and that impaired collagen synthesis.
  • Once again, In elderly people NSAIDs did NOT impair training related tendon adaptations.
  • The inflammatory mediator IL-6 plays a role in stimulating collagen synthesis
  • In tendinopathy, there is no increase in inflammation in the damaged tissue, but more research needs to be done, as it could be a two phase response of early inflammation followed by a degeneration phase.

NSAID therapy effects on healing of bone, tendon, and the enthesis Bailey Su and J. Patrick O’Connor

Building on the previous review Su and O’Connor look at the effects NSAIDs have on healing of the bone and tendon.  Once again, the summary is below:

  • Animal studies consistently show NSAIDs have a detrimental and
    delaying effect on the healing of bone fractures.
  • NSAIDs inhibition of Cox-2 seems to be the culprit
  • Retrospective studies in humans tend to show that NSAIDs
    delay bone healing.
  • NSAIDs may decrease tendon adhesion to the surrounding

Lastly, this review gives a great brief explanation of how tendon and ligaments are healed that deserves a read:

“First, tendon and ligament mechanical strength must be reestablished. Second, tendons must be able to glide freely through the tendon sheath for full range of movement. Third, ligament healing must be sufficient to prevent joint laxity. Finally, in those cases where the tendon or ligament insertion into the bone has been disrupted, this  pecialized junction (enthesis) must be reestablished with functionally equivalent mechanical strength.”

MMP inhibition as a potential method to augment the healing of skeletal muscle and tendon extracellular matrix Max E. Davis,1 Jonathan P. Gumucio,1,2 Kristoffer B. Sugg,1,2,3 Asheesh Bedi, and Christopher L. Mendias1,2

The final review we will go over is by Davis and colleagues which looks at inflammation from a slightly different viewpoint.  It’s a bit more complicated and involves some lesser known aspects of muscle and tendon physiology, so I’ll try to simplify as much as possible.

Instead of focusing on COX inhibitors and what is going on in the muscle or tendon, Davis focuses on enzymes called Matrix metalloprteinasis(MMP) which play a role in maintaining the extracellular matrix(ECM).  The ECM plays a large role in absorption and transmission of force and can be heavily influenced via training.

MMPs  are best thought of as enzymes that break down collagen and clear out the damaged goods. So when an acute injury happens and inflammation occurs, that inflammation triggers MMP activity which then help clear the way and repair damage in the ECM.  If inflammation occurs for too long, then it’s likely that MMPs do too good of a job and disrupts the ECM.

The authors make the case that the balance between collagen synthesis and MMP activity plays a crucial role in chronic injuries.  While it’s complex, the best way to think of it is you have this battle going on between things that break down collagen like MMPs and those that inhibit this breakdown (called TIMPs).  So in the ECM, the key to healthy tissue repair is this balance of collagen production and breakdown.

The ultimate goal should be to clear out damaged ECM andreorganize the collagen in the ECM so that it functions properly.  When this balance is messed up, we run into problems, and the authors suggest that is when tendinpathy occurs. Instead of a nice balance with a smooth network in the ECM, we get a tangled up mess.  The authors suggest that using MMP inhibitors might help with chronic tendinopathy injuries.

The interesting aspect that Davis et al. propose is that once the ECM’s balance is off and the collagen networks become a tangled mess, the ability to sense forces transmitted through the ECM is impaired.  Because it can’t sense the force demand, the body doesn’t know to respond to the loading that the ECM is actually being put under.  So you never get fully repaired.  It’s almost as if the fire alarm stops working, so no one knows to put out the fire.

So What?

Now that we’ve taken a glimpse through the latest research on inflammation and musculoskeletal adaptation, what is the take away?

To me, the first thing I noticed was the incredible complexity that surrounds the question of whether inflammation is good or bad and if we should eliminate it or keep it there. The answer seems to be that it depends. It depends on timing and the type of inflammation, injury, and anti-inflammatory. The overall theme seems to be that there should be a backlash to our anti-inflammatory popping culture.

We’ve swung too far to the black and white thinking that inflammation is something that we always need to get rid of.

Instead, the reality is that the common theme that damage is sometimes a good thing comes into play.  It’s about switching the mindset from thinking that damage is bad to thinking of it as a stimulus for adaptation.  And the goal isn’t to avoid all pain, fatigue, soreness or damage but instead provide the right amount at the right time with enough recovery to provide positive adaptation.

In terms of using NSAIDs, it appears to me that the consensus at this time is that they probably impair at least some muscular and skeletal adaptations.  My advice would be to stay away unless you have a very high amount of acute inflammation.

There are a lot of holes we have to fill before we figure out the best practice, but knowing where the research stands at the moment is important in helping us make our best educated guesses on best practice for our athletes.  Once again, it’s not knowing the exact details of how collagen works or what prostaglandins do.  Instead it’s about knowing the principles.  If we just change the way we look at damage and instead of seeing it as evil see it as a stimulus for something, then we can make the decision on whether or not we want that stimuli or not without even knowing the gory details on COX-2 inhibitors.  Similarly, the principles of balance, and finding the sweet spot instead of only considering the extreme positions is crucial.

(Studies can be found in the current issue of JAP which can be found here:

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