Studies suggest that SS-31 binding to the inner mitochondrial membrane may facilitate the transfer of electrons by inducing curvatures and promoting the construction of respiratory supercomplexes. While reducing electron leak and ROS generation, enhanced forward electron transfer promotes mitochondrial respiration, P/O coupling, and ATP synthesis.
Research suggests that SS-31 may enhance electron transport by enhancing the heme environment of the cardiolipin/cytochrome c complex upon binding to cardiolipin. The release of glutathione bound to proteins in old muscle is compatible with the fast rise in free glutathione in the muscle generated by SS-31, suggesting that SS-31-induced redox regulation may potentially play a role.
Findings of several studies imply there seems to be no change in oxygen consumption between 7- and 30-month-old mice, whereas 30-month-old mice seem to have reduced resting ATP production. As a result, the amount of P/O coupling between mitochondria decreased by half. In older mice, this mitochondrial uncoupling is linked to higher levels of ADP and lower levels of ATP and phosphocreatine. Reversing the loss in mitochondrial function in elderly mice (27 months) with a single concentration of SS-31 was an unexpected finding by Siegel et al.
Research suggests that skeletal muscle may quickly absorb SS-31, reaching maximum levels 30 minutes after presentation. Within 1 hour of SS-31 presentation, maximal ATP synthesis and P/O coupling appeared to have returned to levels seen in 5-month-old mice. SS-31 suggested no discernible impact on young mice; however, it did appear to restore maximum ATP production in older animals. The findings also implied that fatigue resistance may have improved with bioenergetics improvements. Older mice suggested a significant improvement in their endurance capacity after 8 days of presentation with SS-31.
SS-31 Peptide, Diaphragms, and Sepsis
“SS31 prevents sepsis-induced diaphragm dysfunction, preserving force generation, endurance, and mitochondrial function,” reported one research study on SS-31.
Twelve hours of artificial breathing causes diaphragmatic atrophy and contractile failure in rats. Researchers speculate that SS-31 peptide may inhibit mechanical ventilation-induced increases in mitochondrial state 4 respiration, H2O2 release from mitochondria, and oxidative damage to lipids and proteins. Presentation with SS-31, therefore, has been hypothesized to prevent diaphragmatic contractile failure and fiber atrophy. The activation of all important proteases, including calpain, caspase-3, and 20S proteasome activity in the diaphragm, was speculated to be blocked by SS-31, suggesting that mitochondrial oxidative stress may be an essential upstream signal.
SS-31 Peptide and Muscle Cells
In skeletal muscle, 30-month-old mice had substantially decreased maximum ATP generation and mitochondrial coupling efficiency compared to 7-month-old mice. The results indicated a lower energy charge (ATP/ADP) and greater resting ADP. Specialists purported that studies with isolated mitochondria may have suggested an increase in mitochondrial number but a decrease in state 3 mitochondrial respiration and an increase in oxidative damage.
In a recent study, scientists theorized that SS-31 did not appear to have any impact on young mice, but after only 1 hour of presentation, it seemed to return mitochondrial energetics to ‘young’ levels in old mice. Slowly but surely, SS-31 peptide seemed to reverse the age-related reductions in resting and maximum mitochondrial ATP generation, coupling of oxidative phosphorylation, and cell energy status (phosphocreatine/ATP). Reduced glutathione redox status and mitochondrial H2O2 emission were linked to these SS-31 effects in aged muscle. An increase in fatigue resistance was ascertained in elderly mice’s skeletal muscle after a single SS-31 presentation, and whole-body endurance, as assessed by scampering, seemed enhanced after 8 days of presentation. Repairing or replacing damaged mitochondria cannot account for this quick increase in mitochondrial energetics. On the contrary, it implies that SS-31 may have the potential to enhance cardiolipin activity, promote fluidity, and develop supercomplexes on the IMM, all of which contribute to the fast improvement of mitochondrial respiration via increased ETC efficiency.
The potential of SS-31 in disuse atrophy in muscles:
Researchers speculate that disuse atrophy is accompanied by mitochondrial enlargement, increased ROS generation, and reduced respiratory performance of the mitochondria. One possible explanation for the elevated levels of reactive oxygen species (ROS) in mitochondria during inactive atrophy is a rise in fatty acid hydroperoxides and an increase in mitochondrial calcium absorption. Free fatty acids can also raise H2O2 generation and reduce mitochondrial respiration. Muscle atrophy and cardiolipin peroxidation have not been studied; nevertheless, professionals found enlarged mitochondria without cristae membranes in rat soleus muscle after hindlimb suspension. The activation of the intrinsic apoptotic pathway may be explained by cardiolipin peroxidation. According to recent findings, the stimulation of muscle proteolysis may require mitochondrial oxidative stress. Scientific studies have ascertained that SS-31 may potentially prevent disuse atrophy in animal models by increasing mitochondrial respiration and decreasing ROS production.
Click here to be redirected to the Core Peptides website if you are a professional scientist interested in further studying SS-31 peptides.
References
[i] Alam, Nazia M., et al. “A Mitochondrial Therapeutic Reverses Visual Decline in Mouse Models of Diabetes.” Disease Models & Mechanisms, vol. 8, no. 7, 1 July 2015, pp. 701–710, pubmed.ncbi.nlm.nih.gov/26035391/, 10.1242/dmm.020248.
[ii] Lu, Hung-i, et al. “Administration of Antioxidant Peptide SS-31 Attenuates Transverse Aortic Constriction-Induced Pulmonary Arterial Hypertension in Mice.” Acta Pharmacologica Sinica, vol. 37, no. 5, 1 May 2016, pp. 589–603, https://www.nature.com/articles/aps2015162, 10.1038/aps.2015.162.
[iii] Cano Sanchez, Mariola, et al. “Targeting Oxidative Stress and Mitochondrial Dysfunction in the Treatment of Impaired Wound Healing: A Systematic Review.” Antioxidants, vol. 7, no. 8, 24 July 2018, p. 98, 10.3390/antiox7080098.
[iv] Supinski, Gerald S., et al. “SS31, a Mitochondrially Targeted Antioxidant, Prevents Sepsis-Induced Reductions in Diaphragm Strength and Endurance.” Journal of Applied Physiology, vol. 128, no. 3, 1 Mar. 2020, pp. 463–472, 10.1152/japplphysiol.00240.2019.
[v] Wu, Jing, et al. “BDNF Pathway Is Involved in the Protective Effects of SS-31 on Isoflurane-Induced Cognitive Deficits in Aging Mice.” Behavioural Brain Research, vol. 305, 15 May 2016, pp. 115–121, pubmed.ncbi.nlm.nih.gov/26944333/, 10.1016/j.bbr.2016.02.036.
