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'Premature Muscle Aging In Middle-Aged HIV+ men & women'
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Download the PDF here
Download the PDF here
......yet we have little or No research To Understand Better or to Address This, this is not widely discussed/receives NO attention.....muscle biopsies were performed & mid-thigh CT scans in this study, fatigue scores & VACS mortality scores......
"Aging is associated with a seemingly inexorable decline in muscle mass [25], characterized by a notable decline in leg muscle CSA, muscle fiber size, and number [26]. While none of these features were evident in our MATCH cohort, we did, however, observe atypical skeletal muscle cellular profiles suggesting that HIV infection is associated with asynchronous muscle aging. When present, internalized myonuclei can indicate a response to acute injury [27] and accumulate with natural aging, based on reports in healthy adults ≥70 years old [28] and in aged mice [29]. The increased frequency of internalized myonuclei and the reduction in nuclear PGC-1α observed in these middle-aged, currently asymptomatic HIV+ adults may reflect premature features of skeletal muscle aging."
Atypical Skeletal Muscle Profiles in Human Immunodeficiency Virus-Infected Asymptomatic Middle-Aged Adults.....HIV+ men & women, age 5461, <200 viral load, CD4 700-800, 19 years since HIV diagnosis, on integrase, PI or NNRTI: displayed deficits in stair-climb power (P < .001), gait speed (P = .036), and predicted metabolic equivalents, Self-reported fatigue based on the FACIT-F sub scale was significantly higher in HIV+ participants....Asymptomatic HIV-infected middle-aged adults display atypical skeletal muscle profiles, subclinical deficits in physical function, and persistent inflammation and immune activation....The VACS index for all-cause mortality [16] was higher in HIV+ participants compared to uninfected participants.....
This observational study describes a cohort of asymptomatic middle-aged HIV-infected men and women with no evidence for loss in skeletal muscle mass, but that nevertheless have elevated inflammation and immune activation, elevated self-reported fatigue, emerging deficits in physical function, and on muscle biopsy display atypical decreases in skeletal muscle nuclear PGC-1α and elevated internalized myonuclei that are more often seen in elderly uninfected subjects. Previous studies have reported that HIV+ adults experience functional decline more rapidly than expected for their age, with frailty phenotypes occurring at earlier ages [2]. Although these studies have been informative, they have been limited by the absence of concurrent data on skeletal muscle, immune profiles, self-reported fatigue, and physical function assessment.
Computed tomographic scans of the mid-thigh were performed in 63 participants (38 HIV+, 25 HIV-) and did not differ based on HIV status (Figure 3). Further analysis based on Hounsfield unit (HU) thresholds for fat (-190 to -30 HU), low-density muscle (0-34 HU), high-density muscle (35-100 HU), and total CSA (-190 to 100 HU) also did not differ (Supplementary Table 2), suggesting an absence of quantitative loss in muscle mass. However, consistent with prior studies [19] (Supplementary Figure 1), an overall correlation (independent of HIV status) was observed in anterior quadriceps muscle CSA with leg strength and power, and stair-climb power.
Examination of histological sections revealed a significantly increased frequency of mispositioned, internally located myonuclei in HIV+ participants compared with uninfected participants (P < .001; Table 1; Figure 5). The frequency of internalized myonuclei was linearly correlated with immune activation based on expression of HLA-DR on CD8+ T cells (r = 0.396, P = .003) and with CD45+ cells in skeletal muscle (r = 0.489, P = .0004). Notably, internalized nuclei did not correlate with any inflammatory biomarkers (Supplementary Table 3). Because the frequency of CD45+ cells in skeletal muscle did not differ based on HIV status (P = .735), it is unlikely that the elevated internalized myonuclei reflect an inflammatory myopathy. An association was also observed between internalized myonuclei and years since HIV diagnosis (P = .007; Supplementary Table 3).
HIV+ participants displayed a significant reduction in the frequency of PGC-1α-positive myonuclei compared with uninfected participants (P = .006; Table 1; Figure 5; Supplementary Figure 2), suggesting a deficit in bioenergetic capacity. However, there was no evidence for gross mitochondrial pathology based on histologic staining for ragged-red fibers using a Gomori trichrome stain (data not shown).....Internalized myonuclei as a variable was statistically significant independent of composite immune activation and inflammatory scores (OR, 3.14 [95% CI, 1.25-7.85]; P = .015).....When present, internalized myonuclei can indicate a response to acute injury [27] and accumulate with natural aging, based on reports in healthy adults ≥70 years old [28] and in aged mice [29].
Mitochondrial activity declines with aging [22], and deficits have been identified in association with HIV infection [5]. We therefore chose to evaluate mitochondrial bioenergetics by measuring the frequency of muscle myonuclei that were positive for peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), a master regulator of mitochondrial biogenesis [23]. HIV+ participants displayed a significant reduction in the frequency of PGC-1α-positive myonuclei compared with uninfected participants (P = .006; Table 1; Figure 5; Supplementary Figure 2), suggesting a deficit in bioenergetic capacity. However, there was no evidence for gross mitochondrial pathology based on histologic staining for ragged-red fibers using a Gomori trichrome stain (data not shown).
Clinical Infectious Diseases - 1 June 2018
Abstract
Background
Human immunodeficiency virus (HIV)-infected individuals are at increased risk of age-associated functional impairment, even with effective antiretroviral therapy (ART). A concurrent characterization of skeletal muscle, physical function, and immune phenotype in aviremic middle-aged HIV-infected adults represents a knowledge gap in prognostic biomarker discovery.
Methods
We undertook a prospective observational study of 170 middle-aged, HIV-infected ambulatory men and women with CD4+ T-cell counts of at least 350/µL and undetectable plasma viremia while on effective ART, and uninfected control participants. We measured biomarkers for inflammation and immune activation, fatigue, the Veterans Aging Cohort Study mortality index, and physical function. A subset also received a skeletal muscle biopsy and computed tomography scan.
age 56
19 years since HIV diagnosis
less than 200 viral load
Results
Compared to the uninfected participants, HIV-infected participants displayed increased immune activation (P < .001), inflammation (P = .001), and fatigue (P = .010), and in a regression model adjusting for age and sex displayed deficits in stair-climb power (P < .001), gait speed (P = .036), and predicted metabolic equivalents (P = .019). Skeletal muscle displayed reduced nuclear peroxisome proliferator-activated receptor-γ coactivator 1α-positive myonuclei (P = .006), and increased internalized myonuclei (P < .001) that correlated with immune activation (P = .003) and leukocyte infiltration (P < .001). Internalized myonuclei improved a model for HIV discrimination, increasing the C-statistic from 0.84 to 0.90.
Conclusions
Asymptomatic HIV-infected middle-aged adults display atypical skeletal muscle profiles, subclinical deficits in physical function, and persistent inflammation and immune activation. Identifying biomarker profiles for muscle dysregulation and risk for future functional decline in the HIV-infected population will be key to developing and monitoring preventive interventions.
Skeletal Muscle Characterization: Computed tomographic scans of the mid-thigh were performed in 63 participants (38 HIV+, 25 HIV-) and did not differ based on HIV status (Figure 3). Further analysis based on Hounsfield unit (HU) thresholds for fat (-190 to -30 HU), low-density muscle (0-34 HU), high-density muscle (35-100 HU), and total CSA (-190 to 100 HU) also did not differ (Supplementary Table 2), suggesting an absence of quantitative loss in muscle mass. However, consistent with prior studies [19] (Supplementary Figure 1), an overall correlation (independent of HIV status) was observed in anterior quadriceps muscle CSA with leg strength and power, and stair-climb power.
This observational study describes a cohort of asymptomatic middle-aged HIV-infected men and women with no evidence for loss in skeletal muscle mass, but that nevertheless have elevated inflammation and immune activation, elevated self-reported fatigue, emerging deficits in physical function, and on muscle biopsy display atypical decreases in skeletal muscle nuclear PGC-1α and elevated internalized myonuclei that are more often seen in elderly uninfected subjects.
Previous studies have reported that HIV+ adults experience functional decline more rapidly than expected for their age, with frailty phenotypes occurring at earlier ages [2]. Although these studies have been informative, they have been limited by the absence of concurrent data on skeletal muscle, immune profiles, self-reported fatigue, and physical function assessment.
When present, internalized myonuclei can indicate a response to acute injury [27] and accumulate with natural aging, based on reports in healthy adults ≥70 years old [28] and in aged mice [29]. The increased frequency of internalized myonuclei and the reduction in nuclear PGC-1α observed in these middle-aged, currently asymptomatic HIV+ adults may reflect premature features of skeletal muscle aging.
Aging is associated with a seemingly inexorable decline in muscle mass [25], characterized by a notable decline in leg muscle CSA, muscle fiber size, and number [26]. While none of these features were evident in our MATCH cohort, we did, however, observe atypical skeletal muscle cellular profiles suggesting that HIV infection is associated with asynchronous muscle aging.
In contrast with the pre-ART era, an association between an elevated frequency of internalized myonuclei and asymptomatic HIV infection in the current era of effective ART has not been described and quantified [30]. Internalized myonuclei can be a nonspecific feature of muscle disorders, as well as natural aging, making the etiology of the internalized myonuclei currently unclear. Because internalized myonuclei may be an outcome associated with chronic exposure to antiviral drugs, future studies defining ART regimen may be informative. The observed reduction in nuclear PGC-1α may suggest compromised aerobic capacity despite a lack of gross mitochondrial or muscle pathology (based on the absence of ragged-red fibers and fiber type and size distribution).
An increased risk for reduced exercise capacity has been linked to elevated internalized myonuclei and to loss in PGC-1α -dependent gene expression [31]. Mitochondrial DNA mutations have been previously described in skeletal muscle of HIV+ adults on early regimens; although those studies did not include physical function assessment [5]. Future studies comprehensively evaluating mitochondrial bioenergetics, exercise capacity, and intolerance should be informative. As PGC-1α affects neuromuscular junction (NMJ) activity [32], future studies will be needed to determine potential associations between NMJ activity and the atypical skeletal muscle phenotype we are observing in chronic HIV infection.
Cross-talk between immune cell subsets and skeletal muscle tissue is essential for normal muscle maintenance, including for example, muscle cross-talk with monocytes [33], B cells [34], and CD8 T cells [35]. Therefore, a more comprehensive evaluation of this cross-talk will be needed to better define mechanisms underlying dysregulation of immunomyogenic homeostasis in chronic HIV infection.
Prior studies have reported that HIV+ adults experience functional decline that is atypical for their age [2, 36] and, although not a universal finding [13], may be associated with inflammation [12, 15]. In our MATCH cohort, the HIV+ participants displayed elevated CRP, sCD14, and sCD163, but not IL-6, suggesting that this cohort is less advanced in the disablement process, especially given our observation of gait speeds >1.3 meters per second. The complex interaction(s) between comorbid conditions (eg, inflammation, immune activation, myopathy, fatigue) underscore the need for risk indices based on multisystem dysfunction, analogous to existing tools for mortality (ie, VACS index) and frailty [36, 37].
This study extends prior reports of elevated fatigue observed in symptomatic adults with detectable viremia [6] to now include asymptomatic HIV+ middle-aged individuals with undetectable viremia. This raises the concern that, despite the absence of significant differences in muscle mass or CSA, there may be an ongoing accumulation of subclinical deficits.
Prior studies in uninfected adults have reported that age-dependent loss in strength can decline disproportionately to loss in muscle mass [40], indicating that change in muscle mass and strength are not linearly related. Follow-up will be needed to determine the timing and magnitude of loss of muscle mass and its relation to loss in function with aging HIV+ adults. Identifying biomarkers for future impairment that can guide strategies for preventing functional decline in this vulnerable population will likely assume greater importance over time.
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Atypical Skeletal Muscle Profiles in Human Immunodeficiency Virus-Infected Asymptomatic Middle-Aged Adults
DISCUSSION
This observational study describes a cohort of asymptomatic middle-aged HIV-infected men and women with no evidence for loss in skeletal muscle mass, but that nevertheless have elevated inflammation and immune activation, elevated self-reported fatigue, emerging deficits in physical function, and on muscle biopsy display atypical decreases in skeletal muscle nuclear PGC-1α and elevated internalized myonuclei that are more often seen in elderly uninfected subjects. Previous studies have reported that HIV+ adults experience functional decline more rapidly than expected for their age, with frailty phenotypes occurring at earlier ages [2]. Although these studies have been informative, they have been limited by the absence of concurrent data on skeletal muscle, immune profiles, self-reported fatigue, and physical function assessment.
Aging is associated with a seemingly inexorable decline in muscle mass [25], characterized by a notable decline in leg muscle CSA, muscle fiber size, and number [26]. While none of these features were evident in our MATCH cohort, we did, however, observe atypical skeletal muscle cellular profiles suggesting that HIV infection is associated with asynchronous muscle aging. When present, internalized myonuclei can indicate a response to acute injury [27] and accumulate with natural aging, based on reports in healthy adults ≥70 years old [28] and in aged mice [29]. The increased frequency of internalized myonuclei and the reduction in nuclear PGC-1α observed in these middle-aged, currently asymptomatic HIV+ adults may reflect premature features of skeletal muscle aging.
In contrast with the pre-ART era, an association between an elevated frequency of internalized myonuclei and asymptomatic HIV infection in the current era of effective ART has not been described and quantified [30]. Internalized myonuclei can be a nonspecific feature of muscle disorders, as well as natural aging, making the etiology of the internalized myonuclei currently unclear. Because internalized myonuclei may be an outcome associated with chronic exposure to antiviral drugs, future studies defining ART regimen may be informative. The observed reduction in nuclear PGC-1α may suggest compromised aerobic capacity despite a lack of gross mitochondrial or muscle pathology (based on the absence of ragged-red fibers and fiber type and size distribution).
An increased risk for reduced exercise capacity has been linked to elevated internalized myonuclei and to loss in PGC-1α -dependent gene expression [31]. Mitochondrial DNA mutations have been previously described in skeletal muscle of HIV+ adults on early regimens; although those studies did not include physical function assessment [5]. Future studies comprehensively evaluating mitochondrial bioenergetics, exercise capacity, and intolerance should be informative. As PGC-1α affects neuromuscular junction (NMJ) activity [32], future studies will be needed to determine potential associations between NMJ activity and the atypical skeletal muscle phenotype we are observing in chronic HIV infection.
Cross-talk between immune cell subsets and skeletal muscle tissue is essential for normal muscle maintenance, including for example, muscle cross-talk with monocytes [33], B cells [34], and CD8 T cells [35]. Therefore, a more comprehensive evaluation of this cross-talk will be needed to better define mechanisms underlying dysregulation of immunomyogenic homeostasis in chronic HIV infection.
Prior studies have reported that HIV+ adults experience functional decline that is atypical for their age [2, 36] and, although not a universal finding [13], may be associated with inflammation [12, 15]. In our MATCH cohort, the HIV+ participants displayed elevated CRP, sCD14, and sCD163, but not IL-6, suggesting that this cohort is less advanced in the disablement process, especially given our observation of gait speeds >1.3 meters per second. The complex interaction(s) between comorbid conditions (eg, inflammation, immune activation, myopathy, fatigue) underscore the need for risk indices based on multisystem dysfunction, analogous to existing tools for mortality (ie, VACS index) and frailty [36, 37].
This study extends prior reports of elevated fatigue observed in symptomatic adults with detectable viremia [6] to now include asymptomatic HIV+ middle-aged individuals with undetectable viremia. This raises the concern that, despite the absence of significant differences in muscle mass or CSA, there may be an ongoing accumulation of subclinical deficits.
Persistent inflammation and immune activation are established features of chronic HIV infection [38] and effectively discriminate HIV status and comorbid risk [39]. When we considered a cross-platform biomarker profile consisting of inflammation and immune activation, self-reported fatigue (FACIT scores), and all-cause mortality (VACS index), we observed that inclusion of internalized myonuclei increased HIV discrimination (Figure 6; Supplementary Tables 5 and 6).
This study has several limitations. First, the cohort in this study is small (N = 170) and may not be generalizable to all middle-aged HIV+ adults. In addition, although we identified a clear correlation between internalized myonuclei in skeletal muscle and immune activation, we could not detect associations with physical function. This may reflect the healthy status of the participants and currently low penetrance of the muscle phenotype at this time. Longitudinal follow-up with expanded functional assessment may be informative. The muscles sampled (eg, vastus lateralis) may also not fully reflect the functional tests. Additional physical function assessments and biopsy sampling from other muscle groups may be informative. Factors such as current and prior ART regimen use-in particular exposure to early-generation, more toxic therapies-were not fully considered, although in a recent study that included a comparison of nonfrail HIV+ adults with uninfected adults, there were no associations between physical function and differing ART drug use or in total testosterone levels [15]. An ongoing follow-up study assessing prior ART regimen use in MATCH and potential effects on skeletal muscle may be informative.
Prior studies in uninfected adults have reported that age-dependent loss in strength can decline disproportionately to loss in muscle mass [40], indicating that change in muscle mass and strength are not linearly related. Follow-up will be needed to determine the timing and magnitude of loss of muscle mass and its relation to loss in function with aging HIV+ adults. Identifying biomarkers for future impairment that can guide strategies for preventing functional decline in this vulnerable population will likely assume greater importance over time.
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