SLU-PP-332 functions as an exercise mimetic by acting as an agonist at the estrogen receptor-related receptor alpha.
"like another one that's quite trending at the moment that I'm a little hesitant to talk about because it has some potential side effects, but it's called SLU-PP-332. This is another small molecule. It's not a peptide, but it's clumped into them. Um, this works via that estrogen receptor alpha agonism, and they call it exercise in a pill." (said at 0:46:35)
SLU-PP-332 is a synthetic pan-agonist of the estrogen-related receptors (ERRs) with highest potency for ERRα, and has demonstrated exercise-mimetic effects (such as enhanced mitochondrial respiration, increased type IIa oxidative muscle fibers, and improved endurance) in rodent models and cell culture. However, two important qualifications apply: first, the speaker conflated the orphan nuclear receptor 'estrogen-related receptor alpha' (ERRα) with the classical 'estrogen receptor alpha' (ERα), which are distinct receptor systems; second, evidence for SLU-PP-332's exercise-mimetic effects is currently limited entirely to preclinical animal and in vitro studies, with no completed human trials.
- supports: Synthetic ERRα/β/γ Agonist Induces an ERRα-Dependent Acute Aerobic Exercise Response and E… (ACS chemical biology 2023) · cited 43x in the literature
"Here, we report the identification of a synthetic ERR pan agonist, SLU-PP-332, that targets all three ERRs but has the highest potency for ERRα. Additionally, SLU-PP-332 has sufficient pharmacokinetic properties to be used as an in vivo chemical tool. SLU-PP-332 increases mitochondrial function and cellular respiration in a skeletal muscle cell line. When administered to mice, SLU-PP-332 increased the type IIa oxidative skeletal muscle fibers and enhanced exercise endurance." (abstract, results, passage verified)
pubmedfull study (doi) - supports: A Synthetic ERR Agonist Alleviates Metabolic Syndrome. (The Journal of pharmacology and experimental therapeutics 2024) · cited 30x in the literature
"Previously, we described the development of SLU-PP-332, an agonist for the estrogen-related receptor (ERR) α , β, and γ nuclear receptors that activates an acute aerobic exercise program. Here we examine the effects of this exercise mimetic in mouse models of obesity and metabolic syndrome." (abstract, results, passage verified)
pubmedfull study (doi)
Thymosin beta-4 (TB4) fragments interact with actin to help preserve actin in muscle tissue.
"And TB4 fragments also have an effect on actin, which is one of the main um uh proteins in muscle fiber and it helps preserve actin too." (said at 0:54:48)
Thymosin beta-4 (Tβ4) and its actin-binding peptide fragments bind globular monomeric actin (G-actin), which is a principal structural protein in muscle fibers. In cellular physiology, Tβ4 functions primarily as an actin monomer-sequestering peptide, maintaining an unpolymerized G-actin pool and regulating actin filament assembly, sarcomere dynamics, and muscle tissue repair. Describing this biochemical buffering and sequestration mechanism as 'preserving actin' conveys the general role of Tβ4 in maintaining the intracellular actin pool, though its primary biochemical function is the regulation of actin polymerization dynamics rather than passive tissue preservation.
- supports: The actin binding site on thymosin beta4 promotes angiogenesis. (FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2003) · cited 121x in the literature
"It is the most abundant member of the beta-thymosin family in mammalian tissue and is regarded as the main G-actin sequestering peptide... Using naturally occurring thymosin beta4, proteolytic fragments, and synthetic peptides, we find that a seven amino acid actin binding motif of thymosin beta4 is essential for its angiogenic activity." (abstract, results)
pubmedfull study (doi) - context: Aberrant developmental titin splicing and dysregulated sarcomere length in Thymosin β4 kno… (Journal of molecular and cellular cardiology 2017) · cited 11x in the literature
"We sought to determine whether Thymosin β4 (Tβ4), a peptide that regulates the availability of actin monomers for polymerization in non-muscle cells, plays a role in sarcomere assembly during cardiac morphogenesis and influences adult cardiac function... Our data suggest that Tβ4 is required for setting correct sarcomere length and for appropriate splicing of titin, not only in the heart but also in skeletal muscle." (abstract, results, passage verified)
pubmedfull study (doi) - supports: Thymosin beta 10 and thymosin beta 4 are both actin monomer sequestering proteins. (The Journal of biological chemistry 1993) · cited 175x in the literature
"Recently, thymosin beta 4 was identified as a significant actin monomer sequestering protein in cells... Both beta-thymosins bound skeletal muscle actin and inhibited actin polymerization with similar Kd values (between 0.7-1 microM)." (abstract, results)
pubmed