*date*: 2022-06-30 12:03

*L-Citrulline*
nonessential AA that augments #L-Arginine bioavailability, NO production, & performance (primary food source is watermelon)

[1]

Potentially ergogenic to:

[1]

Putative (yet not well supported) mechanisms include ↑blood flow ⇔ vasodilation & skeletal muscle perfusion. [1]

#L-Arginine-NO pathway: L-arginine =(NOS [enzyme])=> #L-Citrulline & NO (NO =(cGMP)=> vasodilation + smooth muscle relaxation) (8) (#L-Arginine + #L-Citrulline > additive [synergistic]) [1]

#L-Citrulline (oral) =(portal circulation)=> kidneys for direct conversion to #L-Arginine (98, 102, 104)

+ #L-Citrulline may enhance #L-Arginine bioavailability by suppressing *arginase* activity (catabolizes #L-Arginine) by acting as a strong allosteric inhibitor. [1]

#L-Citrulline may assist in ammonia detoxification via the urea cycle (ammonia in working muscles promotes fatigue & in blood ↑glycolysis [rate] ⇒ ↑lactate accumulation [fatigue])

*NO synthesis* Augmenting NO synthesis may enhance muscular function, fatigue resistance & recovery processes (8)...

*L-Arginine*

Interestingly, in vitro studies suggest that the Km of the enzyme for L-arginine is in the micromolar range while the concentration for L-arginine (endothelial cells at least) is in the millimolar range, therefore under physiologic conditions, NOS is saturated with its L-arginine substrate (i.e., L-arginine would not be expected to be rate-limiting for NOS).

Yet, #L-Citrulline, and in particular, in combination with #L-Arginine are absolutely ergogenic.

Drugs:

From [2] – Titled, "Sildenafil increases muscle protein synthesis and reduces muscle fatigue":

  1. AAS users were excluded. The interaction between AAS & sildenafil, then, is not studied. It is noteworthy that testosterone (T) via rapid nongenomic pathways (e.g., PKA, PLC, MAPK), can stimulate rapid vasodilation via endothelium -dependent & -independent mechanisms. The former results from increased NO bioavailability via AR-mediated eNOS activation & release of vasodilatory factors into vascular smooth muscle cells... However, T increases renin levels & expression/activity of ACE & AT1R, while downregulating AT2R, thereby favoring a vasoconstrictor pathway, enhances vascular responsiveness to Ang II & may modulate development & maintenance of Ang II-induced hypertension && increased vascular contractility to pressors.

Notably, supraphysiological T in young hypogonadal spontaneously hypertensive rats increases blood pressure, but in aged decreases blood pressure. T status (and therefore AR expression) & age may influence BP response of T.

  1. The treatment (sildenafil, 25 mg p.o. q.d.) group was older (55 ± 11 [26 - 76] years) than the placebo group (44 ± 9 [20 - 68] years), p = 0.436.

Since effects of PDE-5 inhibitors on BP are mediated by NO activity, and there are interactions between testosterone (i.e., AAS), age & BP, there might be some interaction between NO-mediated effects, including effects on muscle fatiguability (implicating calcium channels & eccentric-contraction coupling, redox status, and/or muscle perfusion) that differ by age & by AAS use.

Anyway, back to the study's findings, rather than its significant limitations for us, the ProM readership...

  1. Reduced muscle fatiguability. Sildenafil (25 mg p.o.) was ingested ~ 1 hr pre- dynanometry (to measure isometric torque production, maximal isokinetic power production, & skeletal muscle fatigue of the quadriceps). The significant effect was a reduction in time to fatigue. Practically, this means that when extrapolating to resistance training, the daily low dose PDE-5 inhibitor user (e.g., 25 mg q.d. sildenafil, 10 mg q.d. tadalafil, etc.) may fairly expect to see an increased # of repetitions to failure, and therefore an increased total volume. For those adherents to the belief that training volume is a primary driver of hypertrophy, this is beneficial. For those that, correctly, believe that single fiber muscle tension is the primary driver, this means more repetitions until effective reps are reached, more time in the gym, and more fatigue that complicates recovery/adapatation.
  2. Proposed mechanisms are via effects on calcium channels & eccentric-contraction coupling, redox status, and/or muscle perfusion.
  1. Increased MPS. Muscle protein synthesis increased by ~two-fold in the sildenafil group! This is interesting, and is approximately equivalent to 100 - 200 mg q.w. of testosterone i.m., but rather than increasing muscle mass & strength without affecting fatiguability (like AAS), sildenafil reduces fatiguability with no effect on muscle mass or strength.
  2. Proposed mechanisms are via altered protein synthesis/degradation signaling pathways.
  1. Increased resting metabolic rate. Sildenafil also, interesting, increased RMR, as measured by indirect calorimetry.
  2. Proposed mechanism is a "browning" of white adipose tissue, yielding increased BAT thermogenesis.

https://pubmed.ncbi.nlm.nih.gov/31977835/ #Backlinks 220630-1144.md

*References*: [1] Gonzalez, A. M., & Trexler, E. T. (2020). Effects of Citrulline Supplementation on Exercise Performance in Humans. Journal of Strength and Conditioning Research, 34(5), 1480–1495. doi:10.1519/jsc.0000000000003426 [2] Sheffield-Moore M, Wiktorowicz JE, Soman KV, Danesi CP, Kinsky MP, Dillon EL, Randolph KM, Casperson SL, Gore DC, Horstman AM, Lynch JP, Doucet BM, Mettler JA, Ryder JW, Ploutz-Snyder LL, Hsu JW, Jahoor F, Jennings K, White GR, McCammon SD, Durham WJ. Sildenafil increases muscle protein synthesis and reduces muscle fatigue. Clin Transl Sci. 2013 Dec;6(6):463-8. doi: 10.1111/cts.12121. Epub 2013 Oct 29. PMID: 24330691; PMCID: PMC4076819.