Understanding Muscle Function

One of the most frustrating effects of Mitochondrial disorders is the effect on muscle function.  This can manifest as pain, fatigue, exercise intolerance, involuntary muscle spasms, GI disturbances, incontinence, blindness, weakness and even paralysis.  The toll is not only physical, but also emotionally devastating as impairment worsens and isolation ensues due to decreased functionality.

Unfortunately, not much is done to address these issues.  A better understanding of how muscles work can help direct therapies that could improve muscle functional capacity and overall quality of life.


Muscle cells have multiple nuclei because muscle cells are formed by a grouping of progenitor (stem cell-like) cells fused together to form muscle fibers called Myofibrils.  Myofibrils are segmented into short sections called Sarcomeres which are responsible for the actual contraction and relaxing of muscle tissue.  Within each Sarcomere are alternating layers of two muscle protein filaments.  Actin filaments are wrapped by two proteins called Troponin and Tropomyosin and at rest (in the absence of calcium), these proteins work together to block Myosin binding receptors located along Actin filaments, preventing the initiation of a contraction.  Myosin filaments are lined with multiple Myosin “heads” that bind to open Myosin receptors along Actin, causing muscle contraction.  Muscle contraction, in it’s simplest form, is when Actin and Myosin bridge together, via Myosin heads to Myosin receptors on Actin, and slide past one another causing the shortening of the Sarcomere sections.  This is called the Sliding Filament Model.


In a state of rest, Myosin heads are detached from Actin and contain ADP and an inorganic phosphate molecule; residual from a hydrolyzed (broken down) ATP molecule; a process that breaks the Myosin-Actin bridge from the previous contraction.  Troponin and Tropomyosin work together to block Myosin receptors along Actin filaments.  Myosin heads have returns to the activated or “cocked” position, having harnessed the energy released via hydrolysis of the ATP.

In response to stimuli, motor neurons activate the release of Acetylcholine (ACh).  (For more information on the role of ACh, see below, Understanding Mechanisms of Muscle Paralysis).  ACh triggers sodium ions to enter muscle fiber and potassium ions to exit muscle fiber causing a more positive charge.  Once the “charge” shifts sufficiently, it triggers an action potential that releases calcium ions.  As calcium floods the Sarcomere, it binds with Troponin and changes its structure, rotating the Tropomyosin and revealing Myosin binding sites along the Actin.  The cocked Myosin heads then bind to these receptors and use the energy harnessed from the ATP hydrolysis to pull the Actins toward the center of the Sarcomeres, shortening them into the contracted position.  The ADP and inorganic phosphate are released from the Myosin head during this process.

In order for the contraction to relax and return to a state of rest, the Myosin heads must again release from the Actin, requiring a new ATP molecule to attach to the Myosin head and undergo hydrolysis, again forming ADP and an inorganic phosphate and storing the released energy in the reactivated or cocked Myosin head.  If calcium remains present, the binding sites will remain exposed and the process will repeat, continuing to shorten the Sarcomeres and tighten the muscle contraction.

The following video is an excellent explanation of the mechanisms involved in the Breakdown of ATP and Cross-Bridge Movement During Muscle Contraction (1 min, 50 sec).


A majority of people who suffer from Mitochondrial issues (that naturally involve reduced available ATP) also complain of tense, knotted or cramping muscles that can become so tight and contracted that it is debilitating.  The medical community refers to this as muscle spasticity.  This same muscle “cramping” can be experienced following an intense workout by a perfectly health individual.

This is a direct result of a failure to create sufficient ATP to trigger the mechanism that allows the muscle to relax and return to the neutral position.  In essence, the energy from ATP is used to make the muscle relax.  A failure of this process is the same concept behind rigamortis, as calcium is defused throughout the body muscles contract, but there is no ATP present to allow for the muscle to return to the resting state.

Most medical evaluation begins, as it should, with ensuring proper balance of the key electrolytes of sodium, potassium, calcium.  If spasticity remains unresolved, symptom-management is centered on prescriptions for either muscle relaxers or calcium blockers.  Both options can lead to unwanted complications and cause further damage to Mitochondria and their ability to produce ATP; often the underlying root cause for the muscle tension.

Magnesium (Mg) deficiency is often overlooked as a possible culprit.  In addition to being vitally important to Mito and ATP creation and a cofactor in more than 300 enzymatic reactions, Mg effectuates calcium re-uptake by calcium-activated ATPase of the sarcoplasmic reticulum; thus acting as a natural muscle relaxer.  It can be taken orally (avoid forms that can cause GI upset) and can be absorbed cutaneously by spot treating with Magnesium gel or by soaking in an Epsom salt bath.  There are also non-medication options such as InterX neurostimulation.  The more one can do to limit Mito damage and promote increased ATP production, the more likely one can reduce the impact of muscle spasticity.


It became all the latest craze, Botox.  It temporarily paralyzes muscles making the wrinkles go away.  It has also been used to address excessive sweating by impairing sweat glands and to treat migraines by reducing muscle tension through the same paralytic action.  So how can this application of a toxin increase our knowledge on possible issues associated with Mito induced paralysis?

Botox is produced from a strain of Botulinum toxin known to cause paralysis of muscles.  It does this by blocking the release of Acetylcholine (ACh), a chemical secreted by nerves.  ACh is also associated with proper Mito function, playing an important role in cellular respiration.

As noted above, ACh is an important neurotransmitter to the initiation of proper muscle response to stimuli.  There are several complex processes performed by the body to generate, utilize and recycle ACh.  Shockingly, even different science-based resources seem to each describe biological processes slightly differently.  Therefore, the order of these different processes might be slightly off; but sufficient for a brief overview to explain the different steps:

1.  Creation of Acetyl CoEnzyme A (CoA):  CoA cannot be consumed.  It must be produced by the body.  Pyruvic Acid (from glycolysis), Pantothenate (B5) and Cysteine enter the Mitochondria and, as part of the Krebs cycle, CoA is produced.  This process also requires NAD+ (derived from B3, Niacin), FAD+ (derived from B2, Riboflavin), Lipoic Acid, and Thiamine Pyrophosphate (derived from B1, Thiamine).

2.  Use of CoA to Produce Acetylcholine (ACh):  CoA is used in a variety of ways both in the continued process of the Krebs cycle and in several functions throughout the body.  In relation to muscle function, after exiting the Mitochondria, CoA moves to nerve terminals where it combines with Choline to produce Acetylcholine (ACh), which is stored in Vesicular ACh Transporters.

3.  ACh is an Important Neurotransmitter for Proper Muscle Function:  ACh is a neurotransmitter used to initiate the sequence that allows muscle contraction.  In the presence of sufficient calcium, ACh is released from the Vesicular Transporter and binds to ACh receptors across the synaptic cleft triggering redistribution of sodium and potassium ions.  The resulting change in the charge of the tissue sparks the action potential that initiates the mechanisms involved in muscle contraction (Sliding Filament Model discussed above).

4. Ending ACh Neurotransmission:   To end redistribution of sodium and potassium ions and restore homeostasis in the muscle tissue, ACh must be removed from the synapse and thus end its neurotransmission.  This can occur by ACh diffusing away from the synapse or rapid metabolism by Acetylcholinesterase (AChE), breaking it down into Acetic Acid and Choline.  The Choline is then transported back into the axon terminal for resynthesis to ACh.

In addition to the possibility of insufficient production of ACh which can lead to paralysis of muscles (any deficiency or interference in the process described above), AChE can be inhibited.  This causes ACh to accumulate in the cholinergic synapses which depolarizes the postsynaptic cell and can also eventually lead to muscle paralysis.  AChE inhibition can be caused by:

  • Medications treating:  POTS, Alhzeimer’s, Parkinson’s, Dementia, cognitive impairments including Schizophrenia, Myasthenia Gravis, Glaucoma, Insomnia and decreased REM sleep
  • Caffeine (also blocks Adenosine receptors, reducing the effectiveness of Adenosine; blocks Ionotropic receptors, inhibiting Glycine thereby interfering with physiological processes involving the central nervous system)
  • Pesticides, nerve agents, poisons and venoms (some actions are irreversible or quasi-irreversible)

Muscle Function: Spasticity, Weakness and Paralysis

Bone Health (fighting osteoporosis and other bone disorders)

Joints and Connective Tissue (tendons, ligaments, fascia, skin)

Coming Soon: Migraines

Coming Soon: GI Mobility

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