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  International Workshop
on HIV and Aging
September 23-24, 2021

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Less Healthy Response to Skeletal
Muscle Damage in Older Men With HIV

  International Workshop on HIV and Aging, September 23-24, 2021
By Mark Mascolini for NATAP and Virology Education
Three skeletal muscle changes in people with HIV could be critical to age-related muscle declines, according to results of a biopsy analysis in 30 older men with HIV and 15 matched controls without HIV: (1) higher levels of muscle mitochondrial dysfunction in men with than without HIV, (2) less myofiber regeneration, and (3) more skeletal muscle fibrosis [1]. Frailty and sarcopenia proved much more frequent in these older men with HIV than in the HIV-negative group, but skeletal muscle dysfunction did not clearly explain this greater tendency to frailty or sarcopenia with HIV.
Maintaining skeletal muscle quantity and quality-and thereby avoiding frailty or sarcopenia-is essential to successful aging with or without HIV, Newcastle University researchers reminded HIV and Aging Workshop attendees. Yet little research has closely examined causes and consequences of declining muscle function in people with HIV.
To begin filling this data gap, the Newcastle investigators recruited 30 men with HIV older than 50 years and 15 age- and lifestyle-matched men without HIV. Everyone with HIV was taking a suppressive antiretroviral regimen. With participants under local anesthesia, researchers collected biopsies of tibialis anterior skeletal muscle, which runs down the front of the shin.
The researchers performed the following analyses-by the following methods: mitochondrial analyses-by multiplex fluorescence immunohistochemistry for mitochondrial mass (VDAC1) and electron transport chain complex I (NDUFB8) and complex IV (MTCO1); myofiber type-by multiplex immunohistochemistry for BA-F8 (Type I), SC-71 (Type IIa), and 6H1 (Type IIx); intramyocellular lipid quantification-by BODIPY staining; muscle stem cell (satellite cell) identification-by Pax7 staining; skeletal muscle fibrosis quantification-by Masson's trichrome staining; myofiber degeneration and regeneration--by morphology on haematoxylin and eosin histology; frailty-by Fried frailty phenotype [2]; body composition-by DXA scan.
The 30 men with HIV ranged in age from 50 to 85 years. Among men with HIV, 13% were frail, 50% prefrail, and 37% robust. Respective proportions for the matched HIV-negative men were 0%, 53%, and 47%. Among men with HIV, 17% had sarcopenia, 20% presarcopenia, and 62% no sarcopenia. Respective proportions in the 15 control men were 0%, 0%, and 100%.
Analysis of muscle mitochondrial function detected significantly higher levels of deficiency in mitochondrial complex IV in the HIV group than in HIV-negative controls (P = 0.001). HIV-positive men with the highest levels of mitochondrial complex IV deficiency had levels comparable to those of people with frank mitochondrial disease.
Further analysis documented significantly more muscle fibrosis in men with HIV than in those without HIV (P < 0.0001). And myofiber regeneration in men with HIV significantly lagged that in their HIV-negative counterparts (P = 0.02).
The HIV-positive and negative groups did not differ significantly in abundance of satellite (stem) cells. Men with higher levels of mitochondrial dysfunction had more stem cells (r = 0.49, P = 0.006), and men with more stem cells had higher levels of muscle regeneration (indicating normal healing) (r = 0.52, P = 0.003). But men with more stem cells also had higher levels of muscle fibrosis (indicating abnormal healing) (r = 0.59, P = 0.001).
The Newcastle University researchers concluded that older men with HIV have higher levels of muscle mitochondrial dysfunction than similarly aged men without HIV, and they noted that former use of mitochondria-toxic nucleoside analogs did not explain this difference. Although both frailty and sarcopenia affected higher proportions of men with than without HIV, mitochondrial dysfunction and the other parameters analyzed did not predict frailty or sarcopenia.
Failure to find evidence of a reduced muscle stem cell population in these men with HIV is reassuring, as is evidence that these stem cells play a role in the response to muscle damage, including mitochondrial damage. But men with HIV had less myofiber regeneration than men without HIV and increased skeletal muscle fibrosis.
Overall evidence from this study led the Newcastle team to "conceptualize a less healthy response to muscle damage" in aging men with HIV. They speculated that this deficient response may be driven by an HIV-associated proinflammatory response that may promote fibrosis.
1. Hunt M, Payne B. Skeletal muscle: a critical organ for successful aging in people living with HIV? International Workshop on HIV and Aging, September 23-24, 2021. Abstract
2. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56:M146-56. doi: 10.1093/gerona/56.3.m146.