Sarcopenia and exercise intolerance are major contributors to reduced quality of life in the elderly for which there are few effective treatments. We tested whether enhancing mitochondrial function and reducing mitochondrial oxidant production with SS-31 (elamipretide) could restore redox balance and improve skeletal muscle function in aged mice. Young (5 mo) and aged (26 mo) female C57BL/6Nia mice were treated for 8-weeks with 3 mg/kg/day sS-31. Mitochondrial function was assessed in vivo using 31 P and optical spectroscopy. SS-31 reversed age-related decline in maximum mitochondrial ATP production (ATPmax) and coupling of oxidative phosphorylation (P/O). Despite the increased in vivo mitochondrial capacity, mitochondrial protein expression was either unchanged or reduced in the treated aged mice and respiration in permeabilized gastrocnemius (GAS) fibers was not different between the aged and aged+SS-31 mice. Treatment with SS-31 also restored redox homeostasis in the aged skeletal muscle. The glutathione redox status was more reduced and thiol redox proteomics indicated a robust reversal

Variation in the intensity of fatigue according to selected demographic, cultural, and health/illness variables was explored in 372 patients with HIV/AIDS, and the contribution of fatigue to physical and mental health in this population was investigated within the UCSF Symptom Management Model (UCSF-SMM). The sample included 73% African Americans and 63% males. Moderate to severe fatigue intensity was reported by 58% of the total sample. Women, Hispanics, the disabled and those with inadequate income or insurance reported higher fatigue intensity scores. Two hierarchical regression models explored the contributions of fatigue to physical and mental health. Fatigue contributed 2% to the total variance (37.4%) in physical health, but did not contribute as an independent predictor of the total variance (23.2%) in mental health. The results of this study imply the need for further gender and ethnic-specific fatigue research, as well as symptom cluster research.

HIV-related fatigue continues to be the most common complaint of infected people. No physiological factors have been consistent predictors for fatigue; psychosocial factors, particularly depression, have emerged more consistently in studies. While clinicians would want to rule out common causes of fatigue such as hypothyroidism, hypogonadism, or anemia, there is scant research for most interventions, which makes it difficult to make definitive recommendations for their use. Modafinil has the strongest research evidence to date, with multiple studies finding it effective in relieving fatigue. However, researchers must continue to pursue ways to ameliorate fatigue in HIV infection, given the high financial, personal, and social costs suffered by people experiencing it.

The particular microenvironment of the skeletal muscle can be the site of complex immune reactions. Toll-like receptors (TLRs) mediate inflammatory stimuli from pathogens and endogenous danger signals and link the innate and adaptive immune system. We investigated innate immune responses in human muscle. Analyzing TLR1-9 mRNA in cultured myoblasts and rhabdomyosarcoma cells, we found constitutive expression of TLR3. The TLR3 ligand Poly (I:C), a synthetic analog of dsRNA, and IFN-gamma increased TLR3 levels. TLR3 was mainly localized intracellularly and regulated at the protein level. Poly (I:C) challenge 1) activated nuclear factor-kappaB (NF-kappaB), 2) increased IL-8 release, and 3) up-regulated NKG2D ligands and NK-cell-mediated lysis of muscle cells. We examined muscle biopsy specimens of 6 HIV patients with inclusion body myositis/polymyositis (IBM/PM), 7 cases of sporadic IBM and 9 nonmyopathic controls for TLR3 expression. TLR3 mRNA levels were elevated in biopsy specimens from patients with IBM and HIV-myopathies. Muscle fibers in inflammatory myopathies expressed TLR3 in close proximity of infiltrating mononuclear cells. Taken together, our study suggests an important role of TLR3 in the immunobiology of muscle, and has substantial implications for the understanding of the pathogenesis of inflammatory myopathies or therapeutic interventions like vaccinations or gene transfer.