Can MK-677 (Ibutamoren) Support Muscle Health in Spinal Muscular Atrophy (SMA)?

By SWA

Introduction

Spinal Muscular Atrophy (SMA) is a severe genetic disorder that leads to the progressive weakening and wasting of muscles due to the loss of motor neurons in the spinal cord. The disease is caused by mutations in the SMN1 gene (Survival Motor Neuron 1), resulting in insufficient levels of SMN protein — an essential protein for motor neuron survival. Although there’s a “backup” gene, SMN2, which also produces SMN protein, it only provides minimal compensation due to differences in splicing efficiency.

Modern therapies, including gene replacement therapy (Zolgensma) and SMN2 splicing modifiers (Spinraza and Risdiplam), have dramatically improved outcomes for people with SMA. However, these treatments do not work for all patients and can be costly and invasive. As a result, researchers and clinicians are continually exploring complementary treatments that could improve quality of life and potentially slow disease progression in people with SMA.

One such compound under consideration is MK-677, also known as Ibutamoren. MK-677 is a selective ghrelin receptor agonist that stimulates the release of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) by targeting the ghrelin receptor (ghrelinR), previously known as the growth hormone secretagogue receptor 1a. This receptor binds to ghrelin, a hormone involved in GH secretion, appetite regulation, fat accumulation, and energy expenditure. Although MK-677 doesn’t directly address the genetic cause of SMA, its effects on muscle preservation and metabolism could offer symptomatic relief. Here’s a closer look at how MK-677 might be useful — and where its limitations lie.

The ghrelin receptor (ghrelinR), previously known as the growth hormone secretagogue receptor 1a, is the receptor for the anabolic hormone ghrelin. This hormone is involved in growth hormone (GH) secretion, appetite regulation, fat accumulation and energy expenditure.

Introduction to the ghrelin receptor: https://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=28

How SMA Affects Muscle Health

SMA primarily affects infants and children, leading to progressive muscle weakness, difficulty breathing, and limited mobility. This occurs because the lack of SMN protein impairs motor neuron function and ultimately causes these neurons to die. As motor neurons degenerate, muscles are left without stimulation, which causes them to atrophy, or waste away.

Since SMA’s effects on muscle health are so severe, supporting muscle maintenance becomes a key focus for patients and caregivers. Standard treatments for SMA, like gene therapy and SMN2-splicing drugs, aim to increase SMN protein levels, but they don’t directly target muscle maintenance and growth. That’s where MK-677’s role as a growth hormone secretagogue and ghrelin receptor agonist could offer some potential benefits.

MK-677 (Ibutamoren) Overview

MK-677 is a synthetic compound that stimulates the ghrelin receptor to release growth hormone and increase levels of IGF-1, a hormone that plays a significant role in muscle and tissue repair. By acting as a selective ghrelin receptor agonist, MK-677 mimics the action of ghrelin, a natural hormone known for its role in appetite regulation, fat storage, and energy expenditure.

How MK-677 Works:

  • Activates the Ghrelin Receptor: The ghrelin receptor (ghrelinR), previously known as the growth hormone secretagogue receptor 1a (GHS-R1a), is responsible for binding to ghrelin and initiating various physiological processes related to growth and metabolism. When MK-677 activates this receptor, it signals the pituitary gland to release growth hormone.
  • Increases GH and IGF-1 Levels: The release of GH stimulates the liver to produce IGF-1, a hormone that promotes muscle growth, cellular repair, and bone density. Both GH and IGF-1 are critical for maintaining muscle mass and preventing atrophy.

For people with SMA, these effects could potentially help counteract the muscle wasting and weakness associated with the disease, even though MK-677 doesn’t directly impact SMN1 or SMN2 gene expression.

Potential Benefits of MK-677 for SMA Patients

While MK-677 doesn’t address the genetic root of SMA, its impact on GH and IGF-1 levels could provide indirect benefits in terms of muscle preservation, energy, and quality of life. Here’s a closer look at the potential ways MK-677 could support individuals with SMA.

1. Muscle Maintenance and Growth

One of the primary ways MK-677 might benefit SMA patients is by helping maintain muscle mass. Increased levels of GH and IGF-1 are known to promote muscle anabolism (growth) and reduce muscle catabolism (breakdown). For someone with SMA, this could translate to better muscle strength and endurance, which could help in daily activities and potentially slow down the progression of muscle wasting.

While MK-677 won’t reverse muscle atrophy caused by motor neuron loss, it could help preserve existing muscle and delay further weakening. This symptomatic support could be meaningful, particularly for individuals in the early stages of SMA or those who are already receiving SMN-enhancing therapies.

2. Potential Neuroprotective Effects

Some studies suggest that GH and IGF-1 may have neuroprotective properties, meaning they can help support the health and survival of neurons. IGF-1, in particular, has shown potential in promoting neuronal growth and survival in various neurological studies. For SMA patients, this could mean that MK-677 might provide some degree of protection for motor neurons, although this effect is likely modest at best. It’s worth noting that this benefit remains speculative, as most research on MK-677’s effects has focused on muscle tissue rather than neurons.

3. Improved Quality of Life and Physical Functioning

Individuals with SMA often struggle with limited mobility, fatigue, and difficulty in performing daily tasks. By enhancing muscle tone and energy levels, MK-677 could help individuals with SMA maintain a higher level of activity and better quality of life. Increased GH and IGF-1 levels are associated with improved energy and endurance, which could make physical therapy and daily activities easier to manage.

While these effects won’t change the course of SMA, they could provide meaningful support in improving the daily experience of living with the disease.

Important Limitations and Considerations

While MK-677 offers potential benefits for muscle maintenance and energy levels, it’s essential to understand its limitations, especially in the context of a condition as complex as SMA.

1. MK-677 Does Not Affect SMN1 or SMN2

The root cause of SMA is the lack of SMN protein due to mutations in the SMN1 gene, which cannot be compensated for adequately by the SMN2 gene. MK-677 does not influence SMN1 or SMN2 expression and does not increase SMN protein levels. Therefore, it does not address the fundamental cause of SMA, making it more of a supportive therapy than a treatment.

2. Potential Side Effects

Like any compound that influences hormone levels, MK-677 can have side effects. Common side effects include increased appetite, water retention, and transient blood sugar elevation. Long-term effects on metabolic health and potential risks for insulin resistance should be carefully considered, especially in children or those with pre-existing metabolic conditions.

3. Research on MK-677 and SMA Is Limited

To date, there is little to no direct research on the effects of MK-677 specifically in SMA patients. While we can infer some potential benefits based on its mechanism of action and effects on muscle tissue, further studies are needed to understand how effective or safe MK-677 might be for people with SMA.

Conclusion

In summary, MK-677 (Ibutamoren) holds some promise as a supportive therapy for muscle maintenance and energy enhancement in people with SMA. By increasing levels of GH and IGF-1 through activation of the ghrelin receptor, it may help counteract the muscle wasting and physical decline associated with the disease. However, it’s crucial to recognize that MK-677 does not impact SMN protein levels or address the genetic basis of SMA. For this reason, it should be considered as a complementary option rather than a primary treatment.

As with any experimental treatment, it’s essential for individuals with SMA or their caregivers to consult with healthcare professionals before considering MK-677. While it may offer some quality-of-life improvements, further research is needed to establish its safety, efficacy, and role in supporting SMA patients. For now, gene therapy and SMN2-splicing modifiers remain the mainstay of SMA treatment, with MK-677 potentially serving as a supplemental option in the future.

References:

  1. Kojima M, Hosoda H, Date Y, et al. "Ghrelin is a growth-hormone-releasing acylated peptide from stomach." Nature. 1999;402(6762):656-660. doi:10.1038/45230.
  2. Nass R, Pezzoli SS, Oliveri MC, et al. "Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial." Ann Intern Med. 2008;149(9):601-611. doi:[10.7326/0003-4819-149-9-200811040-00005](https://doi.org/10.7326/0003-
 © 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right.
Library of Congress Card Number: LCN 00-192742
ISBN: 0-9703195-0-9

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