Abstract

Tendinopathy, a common and debilitating musculoskeletal condition, affects athletes, workers, and aging populations worldwide. Despite the prevalence of this degenerative tendon disorder, current treatments remain largely symptomatic, often failing to address the underlying cellular dysfunction driving chronic pain and impaired healing. Recent advancements in mitochondrial biology have revealed the critical role of mitochondrial dysfunction in the pathogenesis of tendinopathy. The mitochondria-targeted peptide SS-31 (elamipretide) has emerged as a novel therapeutic candidate capable of reversing mitochondrial damage, reducing oxidative stress, and promoting tendon regeneration.

This article examines the molecular mechanisms by which SS-31 operates, reviews preclinical evidence from in vitro and in vivo studies, and considers its potential advantages over current therapeutic approaches. Although promising, the translation of SS-31 into clinical practice requires further investigation, including human trials and studies on optimal delivery methods. The emerging paradigm of mitochondrial therapeutics may herald a new era in the management of chronic tendinopathy.

I. Introduction

Tendinopathy, characterized by pain, stiffness, and impaired tendon function, is a major clinical challenge affecting both athletes and the general population. It accounts for a substantial proportion of musculoskeletal injuries, with common sites including the rotator cuff, Achilles, and patellar tendons. Histologically, tendinopathy is marked by collagen disorganization, hypercellularity, neovascularization, and increased apoptosis of tenocytes. Traditional therapies—such as rest, NSAIDs, corticosteroid injections, and physiotherapy—often provide temporary relief but do not effectively address the cellular mechanisms underlying tendon degeneration. As a result, recurrence is common and recovery may be incomplete.

Emerging evidence suggests that mitochondrial dysfunction is a key driver of tendinopathic degeneration. Tenocytes rely heavily on mitochondrial function for energy production, cellular signaling, and apoptosis regulation. Mitochondrial impairment leads to elevated production of reactive oxygen species (ROS), loss of membrane potential, and activation of apoptotic pathways—all of which contribute to tendon cell dysfunction and degeneration. These insights have spurred interest in mitochondria-targeted therapeutics, among which the peptide SS-31 (elamipretide) has shown considerable promise.

SS-31 is a cell-permeable tetrapeptide that localizes to the inner mitochondrial membrane, where it binds to cardiolipin and stabilizes mitochondrial structure and function. Its ability to reduce oxidative damage, enhance ATP production, and promote cellular resilience makes it a compelling candidate for treating mitochondrial-associated diseases, including tendinopathy. This article reviews the role of mitochondria in tendon health, the mechanism of action of SS-31, and recent experimental findings supporting its use as a novel therapy for tendinopathy.

II. Mitochondrial Dysfunction in Tendinopathy

Tendons are mechanosensitive tissues composed primarily of type I collagen and populated by tenocytes—specialized fibroblasts responsible for maintaining extracellular matrix (ECM) integrity. These cells depend on healthy mitochondria for energy, redox balance, and apoptosis control. Under physiological loading, mitochondria help regulate homeostasis by responding to mechanical cues. However, in the context of overuse or injury, mechanical overload and inflammation can disrupt mitochondrial function.

Studies have shown that in tendinopathy, tenocytes exhibit disrupted mitochondrial morphology, including fragmentation and cristae disorganization. Mitochondrial membrane potential is often decreased, and ROS levels are elevated. This oxidative stress damages proteins, lipids, and DNA, further exacerbating cellular dysfunction. Apoptosis of tenocytes and impaired matrix synthesis follow, contributing to the pathological remodeling observed in chronic tendinopathy.

In a recent review by Zhang and Rodeo (2023), the authors emphasized the central role of mitochondria in tendon pathology. They highlighted how mitochondrial dysfunction may precede histological changes and represent an early driver of degenerative cascades. These findings suggest that restoring mitochondrial health could provide a disease-modifying approach to tendinopathy—one that targets the root of the problem rather than its symptoms.

III. SS-31 Peptide: Mechanism of Action

SS-31 (elamipretide) is a synthetic tetrapeptide (D-Arg-Dmt-Lys-Phe-NH2) designed to selectively target the inner mitochondrial membrane. Its unique structure allows it to penetrate cell membranes and concentrate within mitochondria, where it binds to cardiolipin—a phospholipid critical for mitochondrial membrane integrity and function. By stabilizing cardiolipin, SS-31 preserves the architecture of the electron transport chain (ETC) and promotes efficient oxidative phosphorylation.

The primary mechanisms by which SS-31 exerts its protective effects include:

• Reduction of mitochondrial ROS production
• Preservation of mitochondrial membrane potential
• Enhancement of ATP synthesis
• Prevention of cytochrome c release and apoptosis
• Mitigation of inflammation and oxidative damage

Originally developed for cardiovascular and neurodegenerative diseases, SS-31 has demonstrated beneficial effects in models of ischemia-reperfusion injury, diabetic complications, and age-related mitochondrial decline. These findings provide a strong rationale for exploring its application in musculoskeletal conditions characterized by mitochondrial dysfunction, such as tendinopathy.

IV. Experimental Evidence Supporting SS-31 in Tendinopathy

A growing body of preclinical research supports the therapeutic potential of SS-31 in treating tendinopathy. These studies span both in vitro models using human tenocytes and in vivo animal models of tendon degeneration.

A. In Vitro Studies

In a pivotal study published in The American Journal of Sports Medicine (2022), Zhang et al. evaluated SS-31 in cultured tenocytes derived from patients with degenerative rotator cuff tendinopathy. The researchers observed that these cells exhibited mitochondrial fragmentation, decreased ATP production, and elevated ROS levels—hallmarks of mitochondrial dysfunction. Treatment with SS-31 significantly improved mitochondrial morphology, restored membrane potential, and enhanced ATP production. Importantly, SS-31 also reduced oxidative stress markers and decreased apoptosis in tenocytes.

These cellular changes translated into improved collagen production and matrix organization, suggesting that SS-31 not only preserved cell viability but also supported functional tendon regeneration. The findings underscored the importance of targeting mitochondria as a strategy to reverse degenerative changes in tendon cells.

B. In Vivo Studies

In a related study published in The Journal of Bone and Joint Surgery (2022), Zhang and colleagues evaluated the effects of SS-31 in a murine model of supraspinatus tendinopathy induced by mechanical overuse. Mice treated with SS-31 showed significant improvements in tendon histology, including reduced cellular degeneration, improved collagen alignment, and decreased inflammatory cell infiltration. Biomechanical testing revealed enhanced tendon strength and stiffness, indicating functional recovery.

Moreover, SS-31-treated tendons exhibited lower levels of pro-apoptotic markers and oxidative stress indicators, consistent with its role in preserving mitochondrial integrity. These results provided in vivo confirmation of the peptide’s regenerative potential and reinforced the concept of mitochondria-targeted therapy as a viable treatment avenue for tendinopathy.

C. Summary of Findings

Across both in vitro and in vivo models, SS-31 consistently demonstrated the ability to restore mitochondrial function, reduce oxidative damage, and support tendon regeneration. These effects were observed at the cellular, structural, and mechanical levels, suggesting a comprehensive therapeutic impact. The reproducibility of results across multiple models adds to the credibility of SS-31 as a candidate for further development.

V. Advantages of SS-31

Compared to Existing Therapies Conventional therapies for tendinopathy are largely palliative, focusing on symptom relief rather than disease modification. NSAIDs and corticosteroids offer short-term reduction in pain and inflammation but may impair tendon healing when used chronically. Physical therapy and eccentric loading exercises are beneficial but may not be sufficient for severe or chronic cases.

SS-31 represents a fundamentally different approach. By targeting mitochondrial dysfunction—the root cause of cellular degeneration—it offers the potential to modify the disease process itself. Unlike corticosteroids, SS-31 promotes tissue regeneration without impairing matrix synthesis. It may also be compatible with rehabilitation protocols, enhancing the effects of mechanical loading by improving cellular responsiveness.

Furthermore, SS-31’s favorable safety profile and systemic bioavailability make it a promising candidate for both local and systemic administration. Its ability to act on multiple cellular pathways—oxidative stress, apoptosis, and energy metabolism—positions it as a multifaceted therapeutic agent.

VI. Limitations and Challenges

Despite the encouraging preclinical data, several challenges remain before SS-31 can be integrated into clinical practice for tendinopathy. First, no human clinical trials have yet been conducted to evaluate its efficacy and safety in tendon disorders. The optimal dosing regimen, frequency, and route of administration (local injection vs. systemic delivery) require careful investigation.

Second, the pharmacokinetics of SS-31 in tendon tissue are not fully understood. Tendons are relatively avascular, which may limit drug penetration and retention. Developing delivery systems that ensure sustained release and targeted action in tendon tissue will be crucial.

Third, patient heterogeneity in terms of age, activity level, and comorbidities may influence treatment response. Biomarker-based stratification and personalized approaches will be necessary to maximize therapeutic benefit.

Finally, long-term effects and potential off-target actions of SS-31 must be assessed through rigorous safety studies. Although early results are promising, clinical validation is essential.

VII. Future Directions

To advance SS-31 from bench to bedside, several avenues must be pursued. Foremost among these is the initiation of clinical trials evaluating the peptide in patients with chronic tendinopathy. These studies should assess not only pain and function but also imaging and biomarker outcomes to capture underlying biological changes.

In parallel, research should explore combination therapies that pair SS-31 with mechanical loading, growth factors, or gene therapy to enhance its regenerative effects. Novel delivery platforms—such as hydrogels, nanoparticles, or scaffold systems—could improve local retention and bioactivity in tendon tissue.

Finally, a deeper understanding of mitochondrial signaling in tenocytes may identify additional therapeutic targets and guide the development of second-generation mitochondria-targeted drugs. The integration of omics technologies, such as transcriptomics and metabolomics, will facilitate this discovery process.

VIII. Conclusion

Tendinopathy remains a significant clinical burden, with limited options for addressing its underlying cellular pathology. The mitochondria-targeted peptide SS-31 offers a novel and promising therapeutic approach by reversing mitochondrial dysfunction, reducing oxidative stress, and promoting tendon regeneration. Preclinical studies in both human tenocyte cultures and animal models have demonstrated its efficacy across multiple levels of tendon biology.

While the path to clinical translation involves challenges—including optimal delivery, patient selection, and long-term safety—the potential of SS-31 to transform tendinopathy treatment is substantial. As our understanding of mitochondrial biology deepens, therapies like SS-31 may usher in a new era of regenerative medicine for musculoskeletal disorders.

References

1. Works Cited Zhang, Xueying, Ying Zhang, Meng Zhang, Yusuke Nakagawa, Camila B. Caballo, Hazel H. Szeto, Xiang-Hua Deng, and Scott A. Rodeo. “Evaluation of SS-31 as a Potential Strategy for Tendinopathy Treatment: An In Vitro Model.” The American Journal of Sports Medicine, vol. 50, no. 10, 2022, pp. 2805–2816. https://doi.org/10.1177/03635465221107943.
2. Zhang, Xueying, Elizabeth Bowen, Meng Zhang, Hazel H. Szeto, Xiang-Hua Deng, and Scott A. Rodeo. “SS-31 as a Mitochondrial Protectant in the Treatment of Tendinopathy: Evaluation in a Murine Supraspinatus Tendinopathy Model.” The Journal of Bone and Joint Surgery. American Volume, vol. 104, no. 21, 2 Nov. 2022, pp. 1886–1894. https://doi.org/10.2106/JBJS.21.01276.
3. Zhang, Xueying, Ying Zhang, Meng Zhang, Yusuke Nakagawa, Camila B. Caballo, Hazel H. Szeto, Xiang-Hua Deng, and Scott A. Rodeo. “Evaluation of SS-31 as a Potential Therapeutic in the Treatment of Tendinopathy.” Orthopaedic Journal of Sports Medicine, vol. 8, no. 7_suppl6, July 2020. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9339866/.
4. Zhang, Xueying, and Scott A. Rodeo. “Mitochondrial Destabilization in Tendinopathy and Potential Therapeutic Approaches.” Current Opinion in Pharmacology, vol. 67, Apr. 2023, p. 102329. https://www.sciencedirect.com/science/article/pii/S2214031X24001141.