Table of Contents
Introduction
Past Pharmacological Sarcopenia Plays
Anabolic-androgenic steroids (AAS) & Selective androgen receptor modulators (SARMs)
Present Targets
Myostatin inhibitors
APJ receptor agonists
Future Targets
PPARδ
Neuromuscular junction (NMJ)-based therapies
Why sarcopenia matters
Sarcopenia is a progressive, chronic age related loss of muscle mass and muscle function. Nearly everyone experiences sarcopenia at some point in their lifetime, but it typically manifests in a clinically significant manner by the seventh decade of life.
Muscle mass and strength precipitously decline with age, particularly in late life. Source
Sarcopenia affects millions of older adults worldwide; while it may begin insidiously, its consequences become increasingly difficult to ignore as mobility, balance, and overall physical resilience decline—often culminating in disability, frailty, and loss of independence; compared with their non sarcopenic counterparts, those with characteristics of sarcopenia––like low muscle mass, strength, or physical function––are more likely to die from any cause.
In the United States alone, it’s estimated that health complications from adults 60 and older with sarcopenia adds roughly $20 billion to healthcare burden (1, 2). Despite this clear unmet need, there are still no FDA-approved pharmacological therapies for sarcopenia. The only widely accepted intervention for the gradual loss of muscle mass and function with age is the monotone advice of one’s primary care physician: diet and exercise.
Naturally, this stark contrast between the growing unmet need and the lack of effective treatments leads to a key question: why aren’t pharmaceutical companies successfully developing drugs for sarcopenia? In a follow-up piece, we’ll examine the regulatory, commercial, and clinical development barriers that have slowed progress. First, however, it’s important to look at what has been tried thus far. Let’s take a bird’s-eye view of the therapeutic landscape for sarcopenia—past, present, and future.
The past (1950s - mid 2000s)
Anabolic androgenic steroids
This is the androgen receptor.
The androgen receptor is a hormone binding nuclear receptor that lives in the cytoplasm. When anabolic-androgenic hormones bind to it, it swims into the nucleus and acts as a transcription factor, activating several growth-promoting genes downstream of it.
Signaling cascade diagram of androgen receptor. Source
Among this variety of androgen responsive genes are a few familiar names that one might recognize from the literature in aging biology: IGF-1R, mTOR, Akt. These genes are heavily implicated in anabolism, meaning cellular growth, proliferation, and survival. By activating these genes, the androgen receptor tells the cells it's located: Grow! Divide! Use Up Energy!
Anabolic androgenic steroids: the good, the iffy, and the ugly
The good: Anabolic androgenic steroids (AAS), which mimic the activity of native testosterone, are very good at building muscle. Within weeks of continuous administration at supraphysiological levels, their effects on muscle growth become visibly apparent.
A young man’s body composition, before and after 4 months of anabolic steroid usage. Source
Given that AAS are primarily used for hormone replacement or supplementation in a clinical setting, the vast amount of literature on anabolic steroids is under the lens of treating hypogonadal older men; hence, the following data is presented in context of that particular patient population:
Effect of anabolic steroids on muscle mass gain in older men (meta analyses)
These studies show promising results—treatment with anabolic steroids appears to be a highly effective strategy for reversing age-related loss of muscle mass.
The iffy: While anabolic steroids reliably increase muscle mass in sarcopenic individuals, their ability to translate these gains into meaningful and durable improvements in muscle strength is less clear.
Meta-analyses and RCTs suggest modest strength benefits, but these are often confounded by inconsistencies in study quality, heterogeneity in populations (e.g., hypogonadal vs. eugonadal), and the practical significance of observed effects in frail, elderly individuals.
Lee (2023): Eugonadal elderly men experienced more modest improvements in physical function compared to hypogonadal men.
Parahiba (2020): The initially significant effect size of testosterone treatment on handgrip strength (+1.58 kgf [0.17, 3.0]) dropped to a non-significant +0.43 kgf [-2.05, 2.90] after excluding low- to mid-quality studies.
Burrato (2023): Found no significant difference in handgrip strength between placebo and testosterone therapy in older men over 6–12 months.
Isidori (2005): Reported no statistically significant differences between testosterone treatment and placebo for strength measures such as handgrip and leg extension.
These findings suggest that anabolic steroids may have limited efficacy in overcoming the complex physiological barriers to functional strength gains in aging individuals, beyond simply increasing muscle mass.
Effect of anabolic steroids on muscle strength in older men (meta analyses)
The ugly: Unfortunately, targeting the androgen receptor for sarcopenia with AAS opens a can of worms regarding safety.
Outside of skeletal muscle, the androgen receptor is expressed pretty much everywhere in the human body. And AAS don’t care where they bind to: when they come in contact with the androgen receptor, they bind to it––whether that be in the heart, prostate, or liver.
Due to their lack of tissue selectivity, AAS are infamous for causing serious off-target side effects.
In men:
Acceleration in prostate growth and increased risk of prostate cancer
Shrinkage of testes, erectile dysfunction, & infertility
Sex hormones are tied together in a spiderweb of interlinked feedback loops. When men take exogenous androgenic hormones, it causes a cascade of effects - some reversible, some not. Namely, AAS usage acutely suppresses luteinizing hormone, follicle stimulating hormone, and gonadotropin releasing hormone (GnRH).
In turn, suppression of GnRH leads to lower testosterone production in the testicles, in turn leading to the effects of male infertility, testicular atrophy, and azoospermia.
Gynecomastia
Not so fun fact: testosterone readily gets turned into estrogen via aromatase - and higher than normal levels of testosterone therefore means higher than normal levels of estrogen. This altered balance between androgens : estrogens associated with AAS usage will sometimes lead to breast development in men.
Male pattern baldness & acne
In the cell, an enzyme called 5-alpha reductase metabolizes testosterone into dihydrotestosterone (DHT). DHT plays a role in the production of sebum (the stuff that makes hair oily and also the stuff in pimples) and hair follicles. When DHT is elevated, it's implicated with those nasty, manly side effects.
In women, AAS unsurprisingly have masculinizing effects, such as:
facial hair growth
irreversible deepening of voice
alteration of menstrual cycle
clitoromegaly
Cardiovascular safety of anabolic steroids remains elusive: A large longitudinal study of 5,000 testosterone replacement therapy (TRT) patients with existing cardiovascular disease (CVD) found no association between testosterone use and adverse outcomes like heart failure. However, it’s widely known that abuse of anabolic steroids—using doses exceeding therapeutic levels—has been strongly associated with serious cardiovascular risks. Androgen receptor agonism has been linked to dyslipidemia (increased LDL and decreased HDL), left ventricular hypertrophy (thickening of the heart muscle, which reduces its pumping efficiency), elevated blood pressure, and a heightened risk of blood clots due to overproduction of red blood cells (erythropoiesis).
Overall, anabolic androgenic steroids (AAS) reliably increase muscle mass in older men—particularly those who are hypogonadal—and have shown modest strength benefits in meta-analyses; but most importantly––because they lack tissue selectivity–– the safety profile of AAS complicates their viability in being used therapeutically for sarcopenia.
SARMs
Unlike anabolic steroids, selective androgen receptor modulators (SARMs) were invented with a promise: to selectively target androgen receptors in muscle and bone tissues while sparing other organs from unwanted AAS related side effects.
Where did SARMs come from?
The development of SARMs begins with its sister class of hormone therapy - the selective estrogen receptor modulator (SERM). SERMs, such as tamoxifen and raloxifene, revolutionized the treatment of hormone-responsive cancers by selectively modulating estrogen receptors in different tissues. Their success spurred researchers to explore similar strategies for other hormone receptors, leading to the development of SARMs.
Their first obvious use case was to be developed for prostate cancer, an androgen receptor sensitive cancer that in previous time had much cruder treatments (similar to breast cancer before the emergence of SERMs). Bicalutamide, discovered & approved for its role in blocking androgen receptors in prostate tissue, proved to be a worthy scaffold for the development of further SARMs. Unlike traditional anabolic steroids, which affect multiple tissues indiscriminately, bicalutamide demonstrated the potential for selective receptor modulation. This selectivity laid the groundwork for designing other synthetic SARMs that could target specific tissues with greater precision.
The interesting aspect of SARMs is that their “selectivity” can be somewhat misleading. SARMs still interact with androgen receptors throughout the body; however, they exploit subtle differences in androgen receptor coregulators that vary between tissues. This enables them to have greater potency in desired tissues such as bone and muscle, while reducing their potency in other tissues like the prostate.
Unlike anabolic steroids, which equally affect muscle and prostate, SARMs increase the therapeutic efficacy for muscle growth via higher affinity for muscle over prostate. Source
All bark and no bite: the failure of SARMs in achieving FDA approval
Early research showed promising results for SARMs in terms of muscle mass increase and bone density improvements in mice (1, 2, 3, 4, 5); but despite initial excitement, SARMs have not yet lived up to their potential in treating sarcopenia.
Clinical trials have revealed mixed results, with some studies showing modest benefits while others fail to demonstrate significant improvements in muscle function.
Below is a table of compiled efficacy of various SARMs in clinical studies:
As made apparent, SARMs do show promise in potentially increasing lean body mass, but as for increasing muscle function, the clinical evidence is fuzzy.
What is also made apparent is that SARMs are not free of all side effects—at the end of the day, being tissue discriminant is not the same as being truly tissue selective; this is why hormonal changes are still observed with their use, and why they have been explored for use in hormone reliant cancers. Besides suffering from off-target hormonal effects, some SARMs in clinical trials have had issues with liver safety - having transient raises in liver enzymes (1, 2). Due to these side effects overshadowing their benefit, progress in development & approval of SARMs has been very slow moving.
The present (mid 2000s - now)
Myostatin & activin A inhibitors
Few discoveries in the world of muscle biology have garnered as much excitement as the inhibition of myostatin: a powerful regulator of muscle growth.
The discovery of myostatin dates back to 1997 when Se-Jin Lee discovered that a previously unknown gene called GDF-8 played a crucial role in regulating muscle growth. Lee discovered that mice lacking this gene exhibited significant muscle hypertrophy, leading to the realization that GDF-8 (better known as myostatin) acts as a powerful inhibitor of muscle development.
What are myostatin and activin A, and why are they relevant to muscle?
Myostatin and activin A are both members of the TGF-β superfamily, a cluster of proteins highly involved with cell growth and survival, particularly by inhibiting tissue growth.
In muscle cells, these proteins bind to activin type II receptors (ACVR2A and ACVR2B), which then pair with type I receptors to form a complex. This complex initiates a signaling cascade by phosphorylating SMAD2/3 proteins. Once phosphorylated, SMAD2/3 combine with SMAD4 to form a regulatory complex that translocates to the nucleus and modulates gene expression, suppressing muscle growth and regeneration.
In practical terms, this signaling pathway acts as a “brake” on muscle growth. By limiting myocyte proliferation and hypertrophy, myostatin and activin A help ensure that muscle mass doesn’t grow unchecked. However, in conditions like sarcopenia—where muscle loss is a major issue—blocking this pathway could, theoretically, help remove the brakes and restore muscle mass and function.
Myostatin & activin A affect muscle growth by promoting SMAD signaling. Source
Preclinical evidence of blocking the myostatin and/or activin A signaling cascade in mice has been very exciting; it’s shown promise in improving muscle endurance, muscle size + strength, lowers fat mass, and extends lifespan in mice.
Myostatin genetic KO mice have pronounced muscular phenotype. Source
Due to their promise of growing muscle while avoiding the side effects of anabolic
steroids, myostatin & activin A inhibitors have seen a surge of interest from pharmaceutical companies: including some of the biggest ones, like Regeneron and Eli Lilly.
So, Where’s My Anti-Myostatin?!
Clinically, anti-myostatins have come in two different flavors thus far:
Antibody-based antagonists
Antibody-based inhibitors are designed to bind specifically to myostatin and/or activin A, preventing it from interacting with the activin type II receptor.
Ligand traps
Ligand traps are fusion proteins that combine the extracellular domain of the activin type II receptor with a robust immunoglobulin framework, creating a so-called “decoy” receptor; by pretending to be an endogenous receptor to myostatin, ligand traps sequester away myostatin and activin A away from binding to the “true” receptor, kind of like a fishing net!
Receptor Blockades
Receptor blockades like Eli Lilly’s bimagrumab represent another therapeutic approach. These blockades work by inhibiting receptor interactions with ligands while sparing the ligands themselves. This mechanism offers a distinct advantage by reducing the likelihood of off-target side effects that may arise from interfering directly with the ligands.
Left: ligand trap MoA; right: antibody MoA. (1, 2)
Clinical-stage anti-myostatins
Despite the palpable excitement seen in preclinical animal models, myostatin & activin A have not seen as much success in people.
The reason this could be the case, in part, are the following reasons:
1) The myostatin/activin A has multiple built-in redundancies
As I mentioned above, the myostatin/activin A signaling cascade happens through a heterodimer, i.e. two distinct receptors:
Activin receptor type-IIB (ACVR2B)
Activin receptor type-IIA (ACVR2A)
Binding to these receptors causes recruitment of one of the following receptors:
Activin receptor type-IB (ACVR1B)
TGFβ receptor type-I (TGFBR1)
To fully inhibit the signaling cascade, two approaches are possible: block both ACVR2B and ACVR2A, or block the downstream type I receptors, such as ACVR1B and TGFBR1. Each receptor in the pair can compensate for the other, and this has been demonstrated clinically.
The complexity increases further when considering the redundancy of the ligands themselves. Due to the high homology between myostatin and activin A, they can partially compensate for one another. For example, if myostatin is blocked from binding to one of the four receptors mentioned above using a ligand trap, activin A can step in to activate the receptor—and vice versa. For example, Regeneron’s trevogrumab produced only mild effects because blocking myostatin alone allowed ligands like activin A or GDF11 to continue signaling through ACVR2/B.
This suggests that therapies exclusively targeting myostatin—or more broadly, focusing on a single leaf of this complex signaling cascade tree—are less effective in promoting muscle hypertrophy than they might otherwise be.
And lastly: a finer point that’s often overlooked is the translational difference in myostatin/activin A signaling between species. While myostatin is well-known for its role, it is actually less significant in humans and primates compared to mice. Compared to mice, activin A plays a much more prominent role in regulating muscle growth and homeostasis.
2) Inhibition of myostatin during adulthood is not as powerful as genetic embryonic knockout of myostatin
In humans, muscle hyperplasia – the division and proliferation of myocytes – happens during fetal development, and gradually slows to a standstill in early childhood. Interestingly, the most compelling preclinical/observational studies showing increased muscle strength have been in genetic myostatin knockouts (1, 2, 3); and given that myostatin plays a role in embryonic development of muscle fibers, it is possible that this is why strength benefits have not been seen as robustly in adults.
In humans, skeletal muscle hyperplasia ceases in early life. Source
Follistatin: a dark horse path to inhibiting myostatin?
Follistatin is an endogenous inhibitor of myostatin and activin A; in preclinical animal models, its overexpression has been shown to increase muscle mass and strength (1, 2, 3, 4), just like inhibiting receptor binding of myostatin and/or activin A can. Unlike other kinds of myostatin inhibitors––which may only affect one ligand––follistatin’s broader activity could provide a more comprehensive boost to muscle growth by neutralizing multiple inhibitory ligands simultaneously.
Follistatin-derived therapies have reached early clinical trials. Acceleron Pharmaceuticals advanced ACE-083, a locally acting follistatin fusion protein, through multiple studies. While ACE-083 successfully increased the size of targeted muscle groups in both healthy volunteers and patients with rare muscular diseases, it failed to significantly improve muscle function in patients during two Phase 2 trials (1, 2).
Gene therapy approaches to enhance follistatin expression have also been tested in small, open-label clinical trials for rare muscle diseases. Both trials reported improvements in 6-minute walk test (6MWT) scores and localized muscle hypertrophy at the injection site (1, 2). However, these results should be taken with caution due to the small sample sizes, lack of blinding, and the inherent variability of open-label study designs, which can overestimate efficacy.
Debunking Minicircle
Minicircle is a biotech company that advertises the ability to genetically induce overexpression of follistatin in humans via plasmid mediated transfection - a lofty claim. They’ve alleged that this therapy can lower epigenetic age, increase follistatin serum level twofold, and increase fat free mass by 1 - 2 kg, all for the cheery price of $25,000.
Putting digressions about the lack of randomized controls & high likelihood of placebo effect aside, Minicircle is still acting in bad faith by claiming that their delivery platform even works. Max Berry has a solid writeup poking holes in Minicircle's claims of efficacy in detail, but in short its main fatal flaw in claiming to be legitimate is failing a therapeutic dosage sniff test:
→ Plasmid therapy is inherently difficult, because plasmids are not meant to be shoved into cells; both plasmids and cellular membranes have negative electric charges, and repel one another.
-> To get around this, Minicircle uses a polymer called polyethylenimine to bunch up and “hide” the plasmid, so it can be sneaked into cells. Specifically, they used 50 micrograms of polymer, with a ratio of polymer:plasmid of 4:1 (i.e. delivery of around ~12.5 micrograms plasmid).
-> In similar dosage amounts of polymer & DNA, that would lead to a ~500 to 1000-fold change in protein levels (1, 2), done in vivo.
-> Despite this, Minicircle claims that serum FST levels increased only ~twofold. What gives?
APJ receptor agonists
The newest contender on this list! Apelin receptor agonists (often abbreviated as APJ receptor agonists) are ligand agonists of the apelin receptor, a GPCR expressed ubiquitously throughout the human body. They mimic apelin, a peptide implicated in metabolism & nutrient sensing.
APJ has gained excitement as a target for treating sarcopenia because 1) it observationally appears to increase post exercise in humans, a known method of treating sarcopenia; and 2) apelin supplementation reverses sarcopenia in mouse models.
Left: association of greater performance of Short Physical Performance Battery (SPPB) & plasma apelin levels. Right: apelin supplementation protects muscle fiber atrophy in mice with age. Source
Delightfully, we’ve started seeing APJ receptor agonists move towards clinical use. Not long ago, BioAge’s APJ receptor agonist, azelaprag, demonstrated efficacy in alleviating muscle atrophy in healthy volunteers aged 65 and older during a Phase Ib bed rest study; and until recently, were running a Phase II study using it in combination with tirzepatide to treat obesity (unfortunately this study didn’t have the happiest of endings, due to an unfavorable safety signal showing elevated liver enzymes in participants on tirzepatide and azelaprag together).
The leading thought to why APJ receptor agonism potentially has protective effects on metabolism & sarcopenia is that APJ induces mitochondrial biogenesis in skeletal muscle (1, 2, 3). While some studies have implicated that APJr induced mitochondrial biogenesis is mediated via AMPK (the latter of which will be discussed at length in a later section!), this association is mixed (1, 2, 3).
Surprisingly, epidemiological evidence suggests that unlike mice, apelin levels don’t associate as strongly with age, especially in the context of age related sarcopenia (1, 2). On the other hand - it has demonstrated epidemiological association with cardiovascular risk (1, 2, 3), often comorbid with sarcopenia/obesity. Therefore, apelin’s relationship is complex and not necessarily straightforward - and we will have to wait and see if APJ receptor agonists are the real deal.
The future of sarcopenia drug targets
Drugs to improve muscle metabolism & energetics
Despite muscle size and strength being the most common vectors to target with drugs, sarcopenia is not driven by these and these alone; age-related loss of muscle endurance is a quiet but significant driver of sarcopenia and frailty.
Take an oft used fitness metric like Vo2 Max for instance. While not commonly mentioned in the same breath as muscle loss (no pun intended), it still has a very strong relationship with likelihood of all-cause death; declines precipitously with age; and is in part driven due to age-induced declining of muscle quality (1, 2, 3, 4).
Kaplan-Meier curve comparing risk of all-cause death between subjects of different Vo2 Max quintiles. Source
Interestingly––despite being overlooked as a therapeutic option for sarcopenia, there are some clinical hints that suggest how metabolism/endurance boosting drug targets can help protect against sarcopenia. One interesting target of this variety that comes to mind is PPARδ.
PPARδ
Peroxisome proliferator-activated receptor (PPAR) drugs have historically been associated with their role in metabolism and diabetes. Several of the former are already approved (rosiglitazone, pioglitazone, fenofibrate, etc.
PPARδ is an isoform of PPAR, a nuclear receptor implicated in cell survival, differentiation, and metabolism. It is expressed in a wide variety of tissues – from spleen to lung to skeletal muscle.
PPARδ: a member of a fascinating family of nuclear receptors. Source
In the early 2000s, a researcher at the Salk Institute named Ronald Evans discovered that by engineering overexpression of PPARδ in mice, they were able to run for remarkably longer and farther than wild type mice could run; on top of that, they were resistant to high fat diet induced weight gain, too.
PPARδ overexpressing mice have vastly enhanced endurance over WT mice. Source
Excitingly, this finding about PPARδ has held water since Evan’s first paper in mice; the observation of increased running endurance in mice with elevated PPARδ has been independently replicated multiple times, though studies are of varying quality (1, 2, 3, 4, 5).
While still not fully understood in its mechanism of action, the current leading theory is that overexpression of PPARδ shifts energy usage in cells from glycolysis to fatty acid oxidation, dramatically changing how fatigable muscle is. This energy usage “switch” is in turn implicated with a higher concentration of type I muscle fibers – i.e. slow twitch, fatigue resistant skeletal muscle fibers. Similar to apelin, PPARδ has been considered an exercise mimetic; observational studies suggest that exercise upregulates PPARδ (1, 2, 3, 4).
Transgenic mice overexpressing PPARδ have redder muscles, indicating a higher presence of type I, oxygen rich muscle fibers. Source
Smelling an opportunity to develop a first-in-class drug with incredible promise for metabolic disease, GlaxoSmithKline got to work on pushing forward GW50516, a small molecule PPARδ agonist, for metabolic disorders. GW50516 made it as far as Phase II clinical trials, when sadly its path to approval was cut short – a worrisome toxicity signal suggesting the drug had high carcinogenicity in rats stopped development of GW50516 and other PPARδ agonists cold.
Despite concerns over its potential cancer risks, GW50516 has gained a foothold in the performance enhancement community under its new name, “cardarine.” Illicit users praise cardarine for its ability to boost endurance and resilience in sports like cycling and running. Its performance-enhancing effects have even led to controversy, with elite Olympic runners facing penalties for using it to gain a competitive edge.
But is PPARδ activation inherently unsafe? Perhaps not. This year, the FDA approved two PPARδ agonist drugs: Merck’s seladelpar and Ipsen’s elafibranor, both for the treatment of biliary cholangitis. Another called mavodelpar made it as far as Phase 2b without any cancer related safety signals.
Interestingly, the company that sponsored development of mavodelpar also did a leg immobilization study in healthy volunteers, which appears to suggest that PPARδ has a protective effect against muscle wasting.
PPARδ agonist mavodelpar protects against loss of muscle strength in a leg immobility study. Source
These approvals and small suggest that, under controlled and clinical contexts, PPARδ agonists (and other similar targets in this space) may have a place as a pillar of future sarcopenia therapy.
Drugs to promote neuromuscular function
One therapeutic angle for sarcopenia receiving more limelight in recent years is by improving function of the neuromuscular junction.
The neuromuscular junction (NMJ) is the critical interface where motor neurons communicate with skeletal muscle fibers to enable muscle contraction. It acts as a specialized synapse, transmitting signals from the nervous system to muscles through the release of acetylcholine, a neurotransmitter.
In brief, here’s how it works:
1. An electrical impulse (action potential) travels down a motor neuron to the nerve terminal.
2. This triggers the release of acetylcholine into the synaptic cleft.
3. Acetylcholine binds to nicotinic acetylcholine receptors on the muscle fiber membrane (sarcolemma), causing an influx of ions.
4. The ion flow generates a new action potential in the muscle fiber, leading to muscle contraction.
Acetylcholine transmits electrical impulses from nerves to skeletal muscles via the NMJ, enabling muscle contraction. Source
In sarcopenia, the NMJ’s structure and function can deteriorate, contributing to weakened muscle contraction and atrophy. This loss of function also affects motor coordination - as the precise activation of muscles needed for smooth and efficient movement becomes impaired. Reflexes slow down as signal transmission is delayed, making it harder to react quickly to changes in the environment. These issues contribute to difficulties with balance and postural stability, significantly increasing the risk of trips, stumbles, and falls, which are a leading cause of injury and reduced independence in older adults. Everyday activities like walking, climbing stairs, or carrying objects become increasingly challenging, further diminishing quality of life.
Therapeutic strategies aimed at improving NMJ function focus on:
Enhancing acetylcholine signaling
Preventing synaptic degradation
Promoting the repair or regeneration of the NMJ structure
In fact, some drugs targeting the NMJ are already approved for NMJ dysfunction, though not specifically for sarcopenia. Myasthenia gravis, an autoimmune disorder of the NMJ, has several approved treatments that enhance or stabilize NMJ function, such as acetylcholinesterase inhibitors (ACHEIs) - which boost electrical signaling to skeletal muscle via preventing the breakdown of acetylcholine.
Current therapies targeting neuromuscular junction (NMJ) disorders are limited in their ability to address the root cause: denervation, or the progressive loss of nerve connections to muscle fibers. This process involves the degeneration of motor neurons in the spinal cord and peripheral nerves, leading to the disruption of their connections at the NMJ.
Similar to how mature skeletal muscle growth occurs exclusively via hypertrophy of existing muscle, the loss of motor neurons can only be offset by the reinnervation of denervated muscle fibers by neighboring motor neurons. However, this compensatory reinnervation is often incomplete and less efficient, resulting in the formation of larger, less precise motor units (1, 2, 3, 4); consequently, structural change following denervation in net diminishes fine motor control and muscle quality - even with compensatory mechanisms.
Further reading
- https://sarahconstantin.substack.com/p/sarcopenia-experimental-treatments
- https://sens.org/legs-of-iron-feet-of-clay/
- https://trevorklee.com/why-cant-we-just-give-steroids-to-people-with-muscular-dystrophy/
- https://link.springer.com/article/10.1007/s40266-018-0566-y
- AAS: Lipocine
- SARMs: Veru, Viking Therapeutics
- APJ: BioAge
- Myostatin / Activin A: SixPeaks, Regeneron, Versanis (acquired by Eli Lilly), Roche, Keros Therapeutics, Merck (acquired Acceleron), Scholar Rock Therapeutics
- Muscle Metabolism / Exerkines: Mitobridge, Pelagos Pharmaceuticals, Amplifier Therapeutics, Poxel SA
- Miscellaneous: Epirium Bio, Biophytis, Rejuvenate Biomed
