Sarcopenia Related to Human Immunodeficiency Virus: Protective Effects of Exercise

Abstract

We discuss recent evidence supporting the hypothesis that sarcopenia is an emerging health concern among people with HIV due to increasing life expectancy and HIV- and treatment-related comorbidities. We also hypothesize that combined exercise at higher intensity has a key role in managing sarcopenia in this population because it directly (increases muscle strength and stimulates hypertrophy) and indirectly (prevents mitochondrial dysfunction, oxidative stress and persistent inflammation) counteracts sarcopenia hallmarks.

Summary for Table of Contents:

Sarcopenia is increasingly common among people with HIV, and combined exercise at higher intensity is a strategy to prevent its development.

INTRODUCTION

In the three decades since the introduction of antiretroviral therapy (ART), human immunodeficiency virus (HIV) has transitioned into a chronic and manageable health condition. As a result, people with HIV (PWH) are experiencing a life expectancy nearing that of the general population (1). PWH are exposed to persistent HIV and ART toxicity, major mediators of metabolic disturbances such as persistent inflammation and immune activation (2). These disturbances, in addition to prevalent lifestyle and social risk factors (e.g., low levels of physical activity, smoking, substance use), have imposed on PWH an increasing number of non-communicable comorbidities and geriatric syndromes associated with aging (e.g., cardiovascular, metabolic, pulmonary, renal, bone, neurocognitive, malignant disease). Consequently, PWH are diagnosed with major comorbidities and geriatric syndromes up to 16 years earlier than people without HIV (1).

One condition of increasing recognition among aging PWH is sarcopenia. Sarcopenia is a musculoskeletal disease characterized by progressive loss of both skeletal muscle mass and function that is associated with declines in physical function/performance and higher mortality rates in the general population (3). Because of the intersecting effects of aging, HIV, ART toxicity, and some lifestyle and sociodemographic risk factors, PWH are highly susceptible to sarcopenia development. Indeed, sarcopenia may pose a significant health and socioeconomic burden for people with HIV in the coming years due to the increasing life expectancy (primary sarcopenia) and HIV- and treatment-related factors (secondary sarcopenia) (4).

With a lack of effective pharmacological treatments for sarcopenia, exercise has emerged as a key strategy in sarcopenia management. Exercise is considered the most effective intervention for treating sarcopenia in the general population (5). However, the effectiveness of exercise to manage sarcopenia in PWH, and the tolerability of this population to different modes and intensities of exercise, are areas for further research. Our recent studies suggest that combined exercise training (i.e., the combination of aerobic and resistance exercise in the same training session) is the most effective mode of exercise to treat sarcopenia, particularly in older PWH (6, 7). Moreover, emerging data suggest that PWH tolerate higher intensity exercise. This higher intensity may be necessary for optimal strength and physical performance gains, indicating that high-intensity interval training (HIIT) may offer further benefits to this population (6). Our aim is to present and discuss recent evidence supporting the hypothesis that sarcopenia is an emerging health concern among PWH, and that combined exercise at a higher intensity has a key role in managing sarcopenia in this population. First, we describe evidence demonstrating that both aging and HIV management lead to musculoskeletal impairments and sarcopenia in PWH. Second, we discuss the health and socioeconomic burden for PWH that will be realized in the next few years. Finally, we present data supporting the benefits of combined exercise for sarcopenia management in PWH and propose a rationale for the hypothesis that HIIT may improve each sarcopenia parameter (i.e., muscle strength, muscle mass, and physical performance), with direct and indirect beneficial effects on skeletal muscle.

SARCOPENIA, A MUSCULOSKELETAL DISEASE

Sarcopenia is a musculoskeletal disease seen with advanced age and among people with chronic conditions, such as metabolic syndrome, cardiovascular disease, cancer, diabetes mellitus, and HIV (4, 8). Sarcopenia has gained attention in recent years because it is associated with an increased incidence of falls, fractures, physical disability, hospitalization, and mortality in the general population (3). Due to this increased morbidity and mortality, sarcopenia is now recognized as an important illness itself, receiving an International Classification of Diseases code in 2016 (ICD-10 M62.84).

Sarcopenia impacts an estimated 50 million people, with predictions that more than 200 million people will be affected by 2030. As sarcopenia is primarily attributed to aging, the number of people affected by sarcopenia increases at an annual rate of ~0.8% in those older than 50 years. Sarcopenia imposes a significant economic burden associated with both treatment and impact on health care utilization (9). Thus, the clinical and public health implications of unmitigated sarcopenia are high.

The operational definition of sarcopenia has been a matter of debate. Previous definitions were based only on detection of low muscle mass, while a more recent definition considers muscle strength (i.e., handgrip strength) as a primary outcome in sarcopenia diagnosis, acknowledging that muscle strength is better than muscle mass in predicting adverse outcomes (8). Many current definitions of sarcopenia include both low muscle strength and low muscle mass or low muscle quality. Severe sarcopenia is characterized by low muscle mass, low muscle strength, and low physical performance (usually defined as reduced gait speed, reduced lower extremity strength, and impaired balance) (8).

Along with its operational definition, the understanding of sarcopenia has evolved over the last decade. Although sarcopenia is largely attributable to aging, other causes are apparent. Age-related sarcopenia is now considered “primary sarcopenia,” while “secondary sarcopenia” occurs when causal factors other than aging are evident, such as chronic illnesses, physical inactivity, and inadequate intake of energy or protein (8).

SARCOPENIA AS AN EMERGING HEALTH CONCERN AMONG PEOPLE LIVING WITH HIV

PWH are a population highly susceptible to sarcopenia due to a multitude of factors, such as low levels of HIV-1 RNA even with ART, ART side effects, complex sociodemographic risk factors including high rates of smoking and substance use, food insecurity, and physical inactivity, all factors associated with sarcopenia development. Despite that, HIV is rarely considered a risk factor for sarcopenia in guidelines or position papers for the general population (8).

We recently conducted a meta-analysis highlighting a sarcopenia prevalence of 24.1% among PWH (mean age of participants ranged from 35 to 60 years; we included studies defining sarcopenia as low muscle mass, and low muscle mass and strength) (4). Notably, the observation that sarcopenia prevalence was markedly higher in PWH compared to people without HIV (~10% in individuals aged >60 years), and greater than the prevalence observed in many chronic illnesses such as type 2 diabetes mellitus, chronic kidney disease, chronic obstructive pulmonary disease, and obesity. Furthermore, we demonstrated PWH presented 6.1 greater odds of sarcopenia compared to those without HIV infection matched by age (3). Additional factors that contribute to the greater risk of sarcopenia in PWH are summarized in Table 1.

Table 1.

Factors leading to sarcopenia in people living with HIV (PWH).

Primary Sarcopenia
Age-related	↑ Life expectancy ↑ Number of PWH ↑ Older HIV population (nearly half of those living with HIV are now ≥50 years in the U.S. and other countries)
Secondary Sarcopenia
Inflammation	↑ Inflammation (pro-inflammatory state, TNF-α, IL-6, IL1-β) ↑ Reactive oxygen species imbalance (cytochrome P450 2E1 and nicotinamide adenine dinucleotide phosphate) ↑ Mitochondrial dysfunction “Accelerated” aging
Lifestyle factors	↑ Physical inactivity ↑ Sedentary behavior High rates of tobacco and other substance use
Nutrition	↑ Overweight and obese PWH High rates of malnutrition in lower economic contexts Food insecurity
Comorbidity-related	Diabetes Malignancy Chronic Obstructive Pulmonary Disease Cardiovascular disease Liver disease Renal disease HIV and ART

Aging with HIV: Primary Sarcopenia

Over the past two decades, dramatic progress has been made in the prevention, treatment, and care of PWH (1). It is estimated that 38 million people are living with HIV throughout the world. With advances in treatment and care, a longer life expectancy is changing the demographics of the HIV epidemic, and nearly half of those living with well-controlled HIV in the U.S. are now 50 years or older, with similar trends occurring worldwide (10). In the absence of an effective, scalable HIV cure, this population will continue to age and grow. Indeed, estimates predict that the proportion of PWH aged 50 years or older will increase to >70% by 2030 (10). As a result of this increasing life expectancy, we are now seeing the first generation of aging PWH, those who are experiencing the age-associated risk for primary sarcopenia. As PWH age, they are exposed to additional physiologic changes that increase the risk of sarcopenia, including central nervous system decline, increase in catabolic stimuli and reduction in contractile function in muscles, reduced consumption of dietary protein, decreased production of sexual hormones, and others.

HIV- and ART-Related Factors: Secondary Sarcopenia

In addition to the effects of aging, PWH also experience the direct and indirect effects of HIV and the consequences of ART. Consequently, many PWH have metabolic alterations and increased immune activation, resulting in persistent inflammation, elevated reactive oxygen species (ROS) formation, and mitochondrial dysfunction - key factors in sarcopenia development (Figure 1). Indeed, persistent inflammation, ROS imbalance, and mitochondrial dysfunction are implicated as causal factors in HIV-associated sarcopenia (2). Studies have demonstrated that different HIV proteins (i.e., Gp120, Nef, Tat, Vpr) induce the release of pro-inflammatory cytokines (i.e., TNF-α, IL-6, IL1-β) and enhance ROS production mediated upregulation of classical cellular ROS sources (i.e., cytochrome P450 2E1 [CYP2E1] and nicotinamide adenine dinucleotide phosphate [NADPH]) (11). The escalation of pro-inflammatory cytokines and ROS production triggers mitochondrial dysfunction, a key event in muscle loss and sarcopenia, as it inhibits anabolic pathways and activates proteolysis pathways promoting muscle atrophy (12). Although ART suppresses HIV replication, some ART classes (e.g., nucleoside and non-nucleoside reverse transcriptase, and protease inhibitors) trigger ROS production, pro-inflammatory status, and mitochondrial dysfunction (13). Indeed, skeletal muscle mitochondrial dysfunction is central in the muscle degeneration and sarcopenia occurring in PWH.

Figure 1.

Inter-relationship between HIV management, aging and the role of combined and high-intensity exercise in counteracting physiological changes associated with “accelerated” aging in people living with HIV. The aerobic component of combined exercise may counteract persistent inflammation, reactive oxygen species (ROS) imbalance and mitochondrial, dysfunctions that are central in sarcopenia associated with HIV. The resistance component of combined exercise will promote strength gain and increased muscle mass. We hypothesize that a higher intensity of exercise would result in a greater muscle stimulus and greater release of myokines, leading to greater functional benefits. By attenuating those HIV management-associated factors causing sarcopenia, combined and high-intensity exercise may slow down “accelerated” aging, thus preventing secondary sarcopenia, increasing survival expectancy, and enhancing physical functioning, independence, and quality of life (QoL). ART= antiretroviral therapy.

Although these alterations are also observed in older people without HIV, some PWH may experience a phenomenon known as “premature” or “accelerated” aging, where PWH exhibit comorbidities and geriatric syndromes related to aging (including sarcopenia) approximately 16 years earlier than the general population (1,13). This theory is reinforced by DNA methylation studies demonstrating that HIV infection accelerates age-related methylation by approximately 14 years (15). Why PWH experience premature or accelerated aging is not completely understood; study findings suggest that the immune response to HIV and ART is highly inflammatory, which contributes to immunosenescence, a phenomenon described in the literature as “inflammaging.” Among the consequences of accelerated aging, ART-suppressed middle-age PWH exhibit a greater susceptibility to comorbidities that are more commonly observed in older people without HIV, including cardiovascular disease, diabetes, hypertension, osteoporosis, and certain cancers. Ultimately these additional comorbidities and conditions contribute to a greater prevalence of sarcopenia (1, 8, 14).

Fatty infiltration of skeletal muscle (i.e., myosteatosis) occurs with age but also increases following initiation of ART in PWH (16) and occurs more commonly in PWH than people without HIV. Myosteatosis may adversely impact muscle contractile function through mechanical compression and through secreted factors, including hormones and cytokines (17).

In addition to comorbidities, tobacco and other substance use, physical inactivity, and food insecurity or inadequate intake of energy or protein are common among PWH and important factors contributing to secondary sarcopenia in this population. Smoking is associated with enhanced ROS production and persistent inflammation, and smoking is 2 to 3 times more common among PWH than the general population (18). PWH who smoke have decreased immune responses and poorer response and adherence to ART compared to non-smokers with HIV (19); in combination, these factors may contribute to an increased risk of sarcopenia among smokers with HIV. Physical inactivity and sedentary behavior among PWH also contribute to the development of HIV-associated sarcopenia (please refer to important reviews of D. Vancampfort et al. regarding physical activity and sedentary behavior levels among PWH). Only half of PWH comply with the recommended 150 minutes of moderate intensity physical activity per week, lower than in most other populations with chronic diseases. The time PWH spend engaging in sedentary behavior is among the highest levels reported in the literature. PWH experience a range of barriers to engaging in physical activity, such as depression, bodily pain, fatigue, and presence of opportunistic infections.

Finally, the scale-up of effective ART in much of the world has shifted the nutritional status of PWH, from AIDS wasting with profound weight loss and muscle wasting to an increasing prevalence of overweight and obese PWH. In fact, both malnutrition and an obesogenic diet promote loss of muscle mass and muscle quality through different mechanisms and contribute to impaired physical function in PWH. Anorexia due to elevated pro-inflammatory cytokines or opportunistic infections still contributes to wasting in countries where ART is not readily available or is initiated late during the course of HIV (20). In contrast, abdominal obesity has been associated with sarcopenia and frailty in PWH, especially in developed countries (21), and both greater central adiposity and reduced muscle mass have been independently associated with increased five-year mortality in PWH in U.S. (22).

Sarcopenia: a Major Health and Socioeconomic Burden for People With HIV

The impact of sarcopenia can be described at both the individual and population levels. At the individual level, sarcopenia is a debilitating condition that affects overall quality of life and is associated with an increased incidence of falls, fractures, physical disability, risk of hospitalization, and higher mortality rates (8). We expect that this burden is even greater among PWH. Among community-dwelling middle-aged and older adults, sarcopenia was associated with a higher risk of falls at five years (23). As middle-aged PWH (aged 45–65) experience falls at rates similar to those of people 65 or older (24), the impact of sarcopenia on fall risk in PWH or at risk for HIV may be even greater (21, 25). Sarcopenia often occurs concomitantly with bone loss and osteoporosis (21), thus the combination of increased fall risk and greater bone loss frequently seen in PWH may contribute to the greater frequency of fractures in this population (26, 27). Among the general population, people with sarcopenia have a higher odds of all-cause mortality (OR=1.87) than individuals without sarcopenia (3). At the population level, sarcopenia poses a socioeconomic burden for both people with and without HIV. In the U.S., estimates from over 20 years ago (2000) suggest that sarcopenia increases health care expense by at least U.S. $860 or U.S. $933 for men or women, respectively, with sarcopenia (9); these estimates are likely markedly higher today. In Portugal, estimates suggest that sarcopenia increases hospitalization costs by 58.5% for patients aged <65 and 34% for patients aged ≥65 years (28). Although studies on the socioeconomic burden of sarcopenia are limited to populations without HIV, we expect that PWH would experience similar or even more pronounced effects of sarcopenia due to additional risk factors that contribute to higher prevalence and greater severity.

EXERCISE INTERVENTIONS TO COUNTERACT SARCOPENIA IN PEOPLE WITH HIV

Exercise is a key component of sarcopenia management in the absence of effective drugs or other approved protocols. Despite being recognized as an effective strategy for sarcopenia management in the general elderly population (5), we lack evidence examining if exercise to counteract sarcopenia has the same effectiveness in PWH. Because sarcopenia in PWH is the result of multiple complex factors in addition to aging, exercise alone may not be enough to overcome sarcopenia. Indeed, the intersection of aging, HIV, ART side effects, and social aspects may accelerate the occurrence of and exacerbate sarcopenia in PWH (Figure 1). However, recent studies conducted by our group have demonstrated that combined aerobic and resistance exercise, especially when performed at higher intensity, can increase muscle mass, strength, and physical performance in PWH (6, 7). We observe that combined exercise targets the main mechanisms of sarcopenia in PWH and that exercise performed at higher intensity can confer additional benefits. Furthermore, supported by recent evidence in other populations, we expand our findings to hypothesize that the combination of high intensity and interval training may be the most effective tool to counteract sarcopenia in PWH.

Rationale: Combined Exercise to Counteract Sarcopenia in People with HIV

Although resistance exercise alone may appear to be the most beneficial for sarcopenia treatment, because it may directly increase muscle strength and stimulate muscle hypertrophy for muscle mass gain (main sarcopenia components), resistance exercise does not significantly improve aerobic fitness (29, 30). The aerobic component of combined exercise may prevent key mechanisms of muscle loss such as mitochondrial dysfunction, oxidative stress, and persistent inflammation. Indeed, aerobic exercise may exert anti-inflammatory effects by inhibiting pro-inflammatory cytokines – key triggers of muscle proteolysis activation –thus protecting skeletal muscle from atrophy (31). Similar effects are seen in PWH, where exercise attenuates markers of inflammation, including high-sensitivity C-reactive protein, TNF-α, IL-6, and IL-1β (32–34). We, and others, have demonstrated that combined exercise attenuates ART-induced redox imbalance and alleviates oxidative damage in PWH (35, 36). Exercise training promotes mitochondrial biogenesis and enhances mitochondrial dynamics (37), and can partially restore mitochondrial metabolism impaired by ART. Therefore, by diminishing HIV and ART-induced inflammation, ROS imbalance, and mitochondrial dysfunction, combined exercise attenuates muscle wasting, loss of strength, and physical dysfunction, the hallmarks of sarcopenia (Figure 1).

Consistent with our hypothesis in PWH, the World Health Organization physical activity guidelines now cite sufficient evidence to recommend combined aerobic and resistance exercises as effective and suitable for improving health outcomes in PWH (38). Specifically, the guidelines note that combined exercise has moderate evidence for improvement in health-related quality of life and moderate to high evidence for improvements in VO_2max or exercise tolerance, muscle strength, body fat, and lean body mass.

In addition, different modalities of regular exercise help to manage or mitigate different comorbidities in PWH, such as insulin resistance, central adiposity, dyslipidemia, cardiovascular disease, depression, and other conditions that may further contribute to sarcopenia (8, 39). Exercise programs minimize one’s sedentary time, improve ART adherence, and improve the mental health of PWH (38), outcomes that may decrease other risk factors, including smoking or substance use, behaviors associated with increased risk of sarcopenia. Finally, PWH with very low levels of physical activity have greater mortality compared to PWH with moderate and high levels of physical activity (39), an aspect that can be ameliorated with exercise. We propose that combined exercise may prevent or delay sarcopenia development by maximizing physical functioning across the lifespan and minimizing physical dysfunction in older PWH, ultimately decreasing mortality in this population (Figure 2).

Figure 2.

Theoretical model relationship between physical function, aging, and exercise on impaired physical function and mortality risk among people living with HIV (PWH) and without HIV. Sarcopenia and decreased physical function are associated with elevated hospitalization rates, longer hospital stays, and higher mortality rates in the general population. HIV management (effects of HIV itself and antiretroviral therapy side effects) exacerbates physical dysfunction in PWH, which experience sarcopenia and several comorbidities earlier than the general population. In contrast, exercise prevents or delays sarcopenia development by maximizing physical functioning across the lifespan and minimizing physical dysfunction at an older age.

Existing data supports our hypotheses. Recent studies have demonstrated an increase in muscle strength, a primary component of sarcopenia, with combined aerobic and resistance training (6, 7, 38, 40). A study performed by our group demonstrated a significant increase in strength as assessed by the one-repetition maximum test following 16 weeks of combined exercise training (i.e., exercise performed 3 days/week; resistance: 2 to 3 sets of 6 exercises at 8 to 15 maximum repetitions; aerobic: 15 to 20 min of treadmill at 50 to 65% reserve heart rate) (7). PWH experienced significantly increased strength in bench press (+ 12%), leg press (+ 30%), and arm curl (+ 8%), with an overall strength gain of 24% with combined aerobic and resistance training. Combined training also improved total training load for the resistance exercises and increased speed and VO₂ spent during the aerobic component, demonstrating better exercise capacity following the program (41).

Similar improvements in strength are also seen among older PWH. We delivered a 24-week combined aerobic and resistance training intervention (i.e., exercise performed 3 days/week; first 12 weeks consisted of treadmill exercise at 40–50% VO₂ max + 6 resistance exercises at 60–70% of 1-RM; subsequent 12 weeks of treadmill exercise at 60–70% of VO₂max + 6 resistance exercise at >80% 1-RM) to people with and without HIV, aged 50 and older (6, 40). Despite multimorbidity and physical function impairments among these older PWH, our participants improved their overall strength (i.e., handgrip strength and 1-RM for bench press, leg press, and lateral pull-down) and physical performance measures (i.e., 400-meter walk test, stair climb, SPPB, chair stand, and VO₂ maximum). Participants had pre- to post-training increases between 10% (handgrip strength and stair climb) to 45% (bench press) across all variables. In addition to enrolling only older patients, a noteworthy strength of this study was the focus on physical performance outcomes. In contrast, most recent reviews of aerobic and resistance exercise interventions among PWH (we highlight here the important reviews conducted by K. O’Brien et al.) have highlighted a focus on strength, cardiorespiratory fitness, body composition, and immune function rather than physical performance outcomes, such as static balance, gait speed, and lower extremity strength, with studies primarily focused on younger PWH.

Significantly, there was a relatively small gain in lean mass (~0.6 kg) after our combined exercise interventions (7, 40), demonstrating that gains in mass may be more difficult to achieve than gains in strength and exercise capacity among older PWH. Similar results are observed in resistance-only training interventions delivered to PWH (29). These studies suggest that longer intervention periods, higher intensity training, or nutritional counseling/supplementation may be needed to increase muscle mass more effectively in this population. Considering the difficulties in regaining or increasing muscle mass, such results also highlight the importance of maintaining muscle mass among middle-aged PWH. Despite that, evidence shows that combined exercise training has the potential to ameliorate all sarcopenia parameters and to act as a complementary strategy to treat sarcopenia in PWH.

Finally, different types of exercise, including combined exercise, have demonstrated improvement in muscle quality, characterized by decreased fatty infiltration (estimated by computed tomography measured attenuation) in older adults without HIV (42). Although relatively little is known about the impact of exercise on skeletal muscle fat in people without HIV, this is highly relevant considering that lower muscle quality is present in PWH (43) and is likely related to the development of sarcopenia, as has been shown in the general population (6).

High-Intensity Exercise Training as an Emerging Strategy to Counteract Sarcopenia in People with HIV

As the health benefits of exercise tend to increase with increasing exercise dose and duration, one may ask whether the same effects are observed among PWH. We hypothesize that a higher intensity of exercise will result in a greater muscle stimulus and greater release of myokines, leading to greater functional benefits. In the previously mentioned 24-week combined exercise intervention (6, 40), following the initial 12 weeks of moderate-intensity exercise, we randomized participants to continue an additional 12 weeks of moderate-intensity (i.e., exercise performed 3 days/week, at 40–50% VO₂ max and 60–70% of 1-RM) or to advance to a higher intensity of both aerobic and resistance exercise (i.e., exercise performed 3 days/week, at 60–70% of VO₂ max and >80% 1-RM). While this greater intensity had a similar effect in most functional outcomes (i.e., chair stand time, stair climb, handgrip strength, lat pull-down, VO₂max), PWH randomized to high-intensity exercise had the greatest improvements in measures of muscle strength (i.e., 6% and 10% greater in bench and leg press, respectively) and time to complete a 400-m walk (−3%), suggesting that higher intensity exercise may have added benefit in older PWH. Notably, despite being older and with a significant comorbid burden, PWH in this study were not frail and could safely perform a high-intensity exercise; thus, our results may not be generalizable to frail older PWH. Regardless, these findings suggest that sarcopenia in older PWH can be reversed or mitigated with an appropriate stimulus.

Despite the benefits of our intervention, exercise did not completely restore mitochondrial function (6, 40); compared to controls, the mitochondrial adaptations to exercise training (n= 31; 15 PWH) at moderate or high intensity were blunted in PWH as evidenced by significantly smaller increases in citrate synthase activity and protein expression of MnS, PGC-1α, and cytochrome complex (44). Sample size precluded further analysis of an exercise intensity effect on mitochondrial respiration rate and electron transport activity, but these preliminary findings suggest that a stronger exercise stimulus may be necessary to stimulate mitochondrial adaptations in older PWH compared to older uninfected adults. In this regard, we propose that HIIT may confer additional cardiovascular benefits beyond typical continuous moderate-intensity aerobic exercise, as demonstrated in adults with increased cardiovascular disease risk factors (45). Among adults with chronic disease-related fatigue or frailty, supervised HIIT appears safe and may be more effective at improving functional outcomes than low- or moderate-intensity interventions (5). Furthermore, HIIT resulted in better role and social functioning among cancer survivors compared to regular intensity exercise, in addition to being more cost-effective (46); benefits attributed to HIIT can also be replicated to PWH and other populations.

HIIT has both direct and indirect beneficial effects on skeletal muscle. After a single bout of HIIT (i.e., 10 × 1 min sprints at 95% maximal heart rate), resistance (i.e., 3 sets of 10 repetitions of leg extensor and leg press at 95% 1-RM), or aerobic exercise (i.e., 30 minutes at 55%−60% maximal heart rate), both HIIT and resistance exercise increased myofibrillar protein fractional synthetic rate (~55%), while HIIT had additional benefit of increased sarcoplasmic protein fractional synthesis rate (25%) among sedentary older men without HIV (47). A 6-week HIIT intervention (i.e., 5 × 1 min cycling at 124 to 135% of max power output, interspersed by 1½ min of recovery) led to increased mitochondrial content in skeletal muscle of older sedentary people without HIV (48). In a separate study, the combination of HIIT (i.e., 7 × 1 min cycling at 85% peak power) followed by resistance training (e.g., progressive increased load for leg extension, leg press, and squat) for a total of 24 weeks, enhanced skeletal muscle capillarization and oxidative enzyme activity to a similar extent as resistance exercise alone (49), suggesting that the combination of both HIIT and resistance training are highly effective in improving skeletal muscle function with aging. In a 12-week HIIT intervention (i.e., 4 × 4 min at 90–95% of the heart rate peak, interspersed by 4 min of active recovery) including both younger and older adults, robust increases in the amount of mitochondria were seen with HIIT regardless of age; older adults had increases in mitochondrial dynamics but not in mitochondrial content following HIIT, suggesting that older adults may experience greater mitochondrial turnover as a compensatory response (50).

Despite increasing evidence of HIIT benefits among different populations, very little is known about HIIT for older PWH. In a pilot study of four months of HIIT versus continuous high-intensity aerobic exercise (HIIT: four 4-min intervals at 90–95% HRmax separated by a 3-min active recovery at 50–70% heart rate max; high-intensity aerobic exercise: 30–40 min at 70– 80% heart rate reserve; both groups completed two sets of 8–12 repetitions of 6 resistance exercises), older PWH randomized to either group experienced significant improvements in exercise endurance and strength, but not in lean mass (51). Although between-group changes were not compared in this pilot study, these improvements tended to be slightly greater among the HIIT arm, suggesting an added benefit of HIIT. In another study enrolling women with and without HIV (mean age 47 and 42, respectively), a six-week HIIT intervention (i.e., 3 days/week, 8–10 high-intensity and low-intensity intervals on a cycle ergometer at 80%−90% of heart rate reserve) improved exercise capacity in both groups, though to a greater extent among women without HIV (52).

Overall, these data support our central hypothesis that PWH experience greater skeletal muscle impairments and blunted skeletal muscle mitochondrial responses to exercise (44), and require a different exercise dose to restore and achieve levels of cardiovascular fitness and physical function similar to people without HIV. With the direct benefits on cardiorespiratory fitness, mitochondrial dysfunction, and physical function, we believe that HIIT may confer indirect benefits on sarcopenia management through increased muscle strength, function, and mass, specifically in PWH. The safety and efficacy of HIIT in an older population of PWH needs to be confirmed and will be investigated in our ongoing clinical trial High-Intensity Exercise Study to Attenuate Limitations and Train Habits in Older Adults With HIV (HEALTH). In the HEALTH Study, we compare HIIT versus a standard continuous moderate aerobic exercise during 16 weeks of combined exercise training among PWH of 50 years and older (53).

SUMMARY

With a growing number of older PWH, we believe sarcopenia will be a major condition impacting both PWH and health systems, characterized by increased morbidity, healthcare costs, and mortality. Indeed, recent estimates demonstrate an increased odds of sarcopenia among PWH compared to people without HIV. With no approved pharmacologic sarcopenia treatment, physical exercise maintains a key role in sarcopenia management of both PWH and without HIV. Among PWH, we believe that exercise is particularly relevant in sarcopenia management because it is low-cost, feasible, and specifically targets the additional comorbidities that may further hasten sarcopenia. We furthermore propose that HIIT in a combined training regimen provides the most benefit in mitigating sarcopenia, particularly in PWH, while acknowledging that any physical activity can provide benefits in preserving muscle mass and function among aging PWH. Simple steps can encourage goal-setting to increase physical activity levels and ultimately slow sarcopenia with aging (54). Overall, physical activity and exercise counteract the loss of muscle mass and strength, and a greater muscle stimulus likely leads to greater functional benefits.

Key Points.

• Today, people with HIV (PWH) experience a life expectancy close to that of the general population but still demonstrate a lower healthspan. As a result of the intersecting effects of aging, HIV, antiretroviral therapy side effects, and social conditions, this population experiences major comorbidities at an average of 16 years earlier than people without HIV.

• Sarcopenia is a prevalent skeletal muscle comorbidity among PWH and is associated with an elevated risk of hospitalization and mortality; this suggests that sarcopenia will pose a significant health and socioeconomic burden for this population in the coming years.

• With a lack of effective pharmacological treatments for sarcopenia, exercise is recognized as the best way to prevent and treat sarcopenia.

• This review provides a rationale and presents evidence that a combination of aerobic and resistance exercise training, particularly at higher intensity, is the foremost strategy to prevent and mitigate sarcopenia in PWH.