Challenges of rapamycin repurposing as a potential therapeutic candidate for COVID-19: implications for skeletal muscle metabolic health in older persons.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic that has spread worldwide, resulting in over 6 million deaths as of March 2022. Older people have been disproportionately affected by the disease, as they have a greater risk of hospitalization, are more vulnerable to severe infection, and have higher mortality than younger patients. Although effective vaccines have been rapidly developed and administered globally, several clinical trials are ongoing to repurpose existing drugs to combat severe infection. One such drug, rapamycin, is currently under study for this purpose, given its immunosuppressant effects that are mediated by its inhibition of the mechanistic target of rapamycin (mTOR), a master regulator of cell growth. Consistent with this premise, acute rapamycin administration in young healthy humans blocks or attenuates mTOR and its downstream effectors, leading to the inhibition of muscle protein synthesis (MPS). Skeletal muscle mass declines when MPS is chronically lower than muscle protein breakdown. This is consequential for older people who are more susceptible to anabolic resistance (i.e., the blunting of MPS) due to reduced activity, sedentariness, or bed rest such as that associated with COVID-19 hospitalization, and who have also demonstrated a delayed or blunted ability to regain inactivity-induced muscle loss. The lack of studies investigating rapamycin administration on skeletal muscle in older people, and the emergence of effective antiviral medications against severe infection, may indicate the reduced relevance of drug repurposing for present or future pandemics.

INTRODUCTION

In December 2019, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Since then, the virus has spread throughout the world, infecting a minimum estimated 400 million people and causing nearly 6 million deaths at the time of writing (1). Older adults, particularly frail individuals (2) and/or those with preexisting medical conditions, are disproportionately affected by COVID-19 as they are more likely to be hospitalized (3), progress to severe disease (4, 5), and have higher mortality than younger patients (4). Although several highly protective vaccines have been developed and administered on a large scale to help mitigate these risks (6–8), frail older adults are still particularly susceptible to such dangers postvaccination (9). Hence, booster shots have been advised for this population (9, 10) and, with the emergence of new more transmissible variants, the broader public over 12 yr (11). Irrespective of the available vaccine portfolio, continuing efforts are being made to identify candidate medications to treat active infection, which may continue into the foreseeable future with viral mutants and/or novel emergent viruses that may evade immunization or current disease-specific antiviral medications. Drug repurposing (i.e., the use of pharmacotherapies that have been approved for alternative illnesses against SARS-CoV-2 infection) forms a key part of this strategy (12–14) as it is cost-effective, less time-consuming, and uses existing validated information about the pharmacokinetics and dynamics of a given candidate drug (13, 15).

Over the past 2 years, several reviews have advocated the use of rapamycin and its derivatives (i.e., rapalogs) as drug repurposing candidates against COVID-19 (13, 16–19). Rapamycin (also called sirolimus) is a natural macrolide compound first isolated from the Streptomyces hygroscopicus bacterium that was discovered on the island of Rapa Nui in 1972 (20). Rapamycin functions as an immunosuppressant through inhibition of the mechanistic target of rapamycin (mTOR), an important serine/threonine protein kinase that regulates a diverse array of metabolic and proliferative processes within the eukaryotic cell (21, 22). mTOR exists in two complexes, of which rapamycin primarily targets mTOR complex 1 (mTORC1), a master regulator of cell growth (21). The premise for the use of rapamycin as a COVID-19 therapeutic holds that mTOR inhibitors may reduce the potential for COVID-19-induced cytokine storms (a major cause of serious illness, potentially irreversible tissue damage, and death) and lessen the severity of infection in critical patients (17, 23). The protective effects of rapamycin are achieved, in part, by attenuating T cell hyperreactivity and mitigating the downregulation of regulatory T cells (23). Therefore, rapamycin and its derivatives could ostensibly offer value as drug repurposing candidates against the development of severe diseases resulting from COVID-19 infection.

The commencement of large-scale clinical trials of mTOR inhibitors in patients with COVID-19 has recently been encouraged (18, 19). Indeed, at the time of writing, there are four active registered trials using rapamycin in such a manner (ClinicalTrials.gov Identifiers: NCT04461340, NCT04341675, NCT04374903, NCT04948203). Perhaps understandably, all these studies include older adults in their selection criteria, owing to the elevated and disproportionate risk of COVID-19 to this population. Beyond its role as an immunosuppressant, rapamycin has several impactful effects due to its specific action on mTORC1, one of which is the inhibition of protein synthesis. This is of relevance for skeletal muscle, a fundamentally important tissue that constitutes ∼40% of total body weight and ∼20% of resting metabolic rate, which experiences a progressive loss in mass, strength, and function with aging. These losses, collectively referred to as sarcopenia (24, 25), are accelerated after 60 yr (26) and are prevalent in 10%–27% of people over this age (27). Sarcopenia places a significant financial burden on the healthcare system (∼$40.4 billion per annum in the United States) (28), as individuals with sarcopenia are almost twice as likely to be hospitalized. Furthermore, low muscle mass has been reported to be an independent risk factor for mortality (29), including after hospital discharge (30). The administration of rapamycin, a compound shown to inhibit protein synthesis in acute human studies (31–33), may thus exacerbate muscle losses in a population with preexisting vulnerability to this phenomenon.

Here, we discuss the potential implications of rapamycin administration for skeletal muscle metabolic health in older patients with COVID-19, using evidence from human trials. Furthermore, we reaffirm the importance of mTOR signaling in the regulation and maintenance of skeletal muscle mass from an aging perspective.

ACUTE RAPAMYCIN ADMINISTRATION IN HUMANS: EFFECTS ON SKELETAL MUSCLE METABOLISM

Skeletal muscle mass in humans is primarily determined by muscle protein synthesis (MPS) as the main constituent of daily net balance, the chronic suppression of which will invoke sarcopenia in older adults (34). A small number of seminal studies (31–33, 35) have explored the effects of acute rapamycin administration on skeletal muscle anabolic signaling and MPS in young adults. These studies were integral in developing our understanding of the role of mTORC1 in the regulation of skeletal muscle mass in response to exercise and nutrients in humans.

The first study administered 6 mg rapamycin versus placebo under conditions of hyperaminoacidemia, low peripheral hyperinsulinemia (∼100 pmol/L), and prandial-like peripheral hyperinsulinemia (∼450 pmol/L) (35). Combined hyperaminoacidemia and prandial-like peripheral hyperinsulinemia increased skeletal muscle S6K1 and IRS-1 phosphorylation (downstream targets of mTORC1) in the placebo group, but rapamycin partially inhibited these effects, thus partially ablating the mTOR pathway. In a subsequent study, participants ingested 12 mg rapamycin 2 h before commencing a bout of resistance exercise (31). The characteristic increase in MPS seen 1–2 h immediately following resistance exercise in a control group (∼40%) was abolished with rapamycin ingestion. Furthermore, the contraction-induced activation of mTORC1-associated signaling components (i.e., mTOR, S6K1, rpS6, eEF2) was either delayed or blocked by rapamycin administration. It is also important to note that no effects on basal MPS were observed in these studies.

A further two studies from the same research group investigated the acute effects of a larger single-dose (16 mg) of rapamycin in young volunteers (32, 33). The indispensable role of mTORC1 signaling in the dietary essential amino acid (EAA)-induced stimulation of MPS was demonstrated by Dickinson et al. (33), wherein rapamycin completely blocked the ∼60% postprandial increase in MPS seen following ingestion of 10 g EAAs in a control group. Consistent with Drummond et al. (31), rapamycin also attenuated or negated the activation of mTORC1-associated signaling proteins. The most recent study, to our knowledge, of acute rapamycin administration in humans found a reduction in mTOR and S6K1 phosphorylation and inhibition of MPS following blood flow-restricted low-intensity resistance exercise compared with controls (32). Taken together, these findings highlight the inhibitory action of rapamycin on the molecular activation and manifestation of MPS in healthy young volunteers.

POTENTIAL IMPLICATIONS OF RAPAMYCIN ADMINISTRATION FOR SKELETAL MUSCLE HEALTH IN OLDER PERSONS

To date, no study has investigated the effects of acute rapamycin administration on skeletal muscle anabolic signaling and MPS in older persons. Nevertheless, the available literature on healthy young adults underlines the importance of mTORC1 signaling for elevated MPS in response to anabolic stimuli (i.e., muscle contraction/mechanical loading, EAAs, growth factors/insulin) in humans and the inhibitory role of rapamycin on these mechanisms. Importantly, older people tend to require a greater degree of anabolic stimulus to obtain similar increases in MPS to those seen in the young, be that contraction-induced activity (36) or the consumption of dietary protein/EAAs (37, 38). This anabolic resistance exists as a “dimmer switch” (39, 40) that is amplified by as little as 2 wk of reduced activity (41), sedentariness, or short-term (∼7–14 days) bed rest (42, 43), which is comparable to the median hospital length of stay for patients with COVID-19 (44). In fact, overweight prediabetic older adults fail to recover baseline rates of MPS following 2 wk of step-reduction, even after returning to normal activity (45). As COVID-19-associated reductions in global physical activity levels already threaten skeletal muscle health, it is imperative to offset any further detriments that may augment these phenotypes. Therefore, strategies are needed to either protect the muscle during periods of inactivity or disuse and/or successfully “re-sensitize” the muscle to anabolic stimuli in the COVID-19 postrecovery phase.

The authors can only speculate that the detrimental skeletal muscle health effects of acute rapamycin may be more pronounced in older and/or sedentary individuals than in their healthy young counterparts. The ongoing clinical trials of rapamycin for COVID-19 are currently implementing dosage protocols that are substantially lower than those administered in acute studies of skeletal muscle metabolism (e.g., 4–6 mg loading dose followed by 0.5–2 mg daily for 9 days, 14 days, or hospital discharge). However, it should be noted that the elimination half-life of rapamycin is relatively long [62 ± 16 h in patients with renal transplant (46)], and when allied to the median length of hospital stay with COVID-19 of up to 14 days, depending on country of residence (44), an increasing exposure to the drug will be inevitable with successive daily ingestion.

To our knowledge, no study has investigated the effects of chronic rapamycin administration on skeletal muscle health in humans. Although rapamycin is safe and feasible for ingestion in healthy older people (75–90 yr; 1 mg/day) for 8 wk, it is not without adverse side effects (e.g., facial rash, stomatitis, and gastrointestinal issues) according to prior research (47). Skeletal muscle metabolic characteristics were not measured and the adverse impact of twice this daily dose (as per the ongoing clinical trials) is unclear. Furthermore, this study was conducted in healthy older adults, not patients with COVID-19 in a hospital setting that are likely to present with anabolic resistance (42). Evidently, a risk/benefit trade-off must be considered with regard to the potential adverse effects on skeletal muscle health versus the potentially beneficial implications for surmounting severe COVID-19 infection. At the very least, an argument can be made to include follow-up skeletal muscle metabolic assessments in the planned and ongoing clinical trials, so that the opportunity to address these research concerns is not lost. With the emergence of new and highly effective oral antiviral drugs such as Paxlovid (48, 49) for the treatment of severe COVID-19 infection, the rationale for rapamycin repurposing is further diminished as these antivirals are likely to be more efficacious and/or have less side effects.

SUMMARY AND PERSPECTIVES

The urgency to find and repurpose efficacious drugs against COVID-19 is understandable and warranted given the impact and ongoing challenges posed by the global pandemic. However, this resolve must be tempered with an appreciation of the known effects of a given medication on fundamental components of human health. The authors of this review do not have a definitive answer as to the safety of acute or chronic rapamycin administration for skeletal muscle health in older patients with COVID-19, due to the paucity of literature on the topic. It is evident, however, that adequate strategies should be in place to ensure that older patients do not successfully recover from COVID-19 to face a new challenge that poses severe implications for skeletal muscle strength, mass, quality, and overall health. Given that older adults may experience a blunted ability to recoup inactivity-induced muscle losses that are thought to underpin or accelerate sarcopenia, we propose that postdischarge muscle rehabilitation should be a high priority for older patients receiving rapalogs and included as part of their full medical treatment plan.

GRANTS

D.R.M. is supported, in part, by Natural Sciences and Engineering Research Council Discovery Grant RGPIN-2015–04251.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

M.J.L. conceived and designed research; M.J.L. drafted manuscript; M.J.L., N.H., C.T.T-G., H.J.W.F., A.E., and D.R.M. edited and revised manuscript; M.J.L., N.H., C.T.T-G., H.J.W.F., A.E., and D.R.M. approved final version of manuscript.