The contributions of fibre atrophy, fibre loss, in situ specific force and voluntary activation to weakness in sarcopenia

The contributions of fibre atrophy, fibre loss, in situ specific force and voluntary activation to weakness in sarcopenia remain unclear. To investigate, forty older (20 women; age 72±4yrs) and 31 younger adults (15 women, age 22±3yrs) completed measurements. The knee extensor maximal voluntary torque (MVC) was measured as well as voluntary activation, patella tendon moment arm length, muscle volume and fascicle architecture to estimate in situ specific force. Fibre cross-sectional area (FCSA), fibre numbers and connective tissue contents were also estimated from vastus lateralis biopsies. The MVC, quadriceps volume and specific force were 39%, 28% and 17% lower, respectively, in old compared with young, but voluntary activation was not different. The difference in muscle size was due in almost equal proportions to lower type II FCSA and fewer fibres. Five years later (n=23) the MVC, muscle volume and voluntary activation in old decreased an additional 12%, 6% and 4%, respectively, but there was no further change in specific force. Conclusions: in situ specific force declines relatively early in older age and reduced voluntary activation occurs later, but the overall weakness in sarcopenia is mainly related to loss of both type I and II fibres and type II fibre atrophy

Mitochondrial function as a determinant of life span

Average human life expectancy has progressively increased over many decades largely due to improvements in nutrition, vaccination, antimicrobial agents, and effective treatment/prevention of cardiovascular disease, cancer, etc. Maximal life span, in contrast, has changed very little. Caloric restriction (CR) increases maximal life span in many species, in concert with improvements in mitochondrial function. These effects have yet to be demonstrated in humans, and the duration and level of CR required to extend life span in animals is not realistic in humans. Physical activity (voluntary exercise) continues to hold much promise for increasing healthy life expectancy in humans, but remains to show any impact to increase maximal life span. However, longevity in Caenorhabditis elegans is related to activity levels, possibly through maintenance of mitochondrial function throughout the life span. In humans, we reported a progressive decline in muscle mitochondrial DNA abundance and protein synthesis with age. Other investigators also noted age-related declines in muscle mitochondrial function, which are related to peak oxygen uptake. Long-term aerobic exercise largely prevented age-related declines in mitochondrial DNA abundance and function in humans and may increase spontaneous activity levels in mice. Notwithstanding, the impact of aerobic exercise and activity levels on maximal life span is uncertain. It is proposed that age-related declines in mitochondrial content and function not only affect physical function, but also play a major role in regulation of life span. Regular aerobic exercise and prevention of adiposity by healthy diet may increase healthy life expectancy and prolong life span through beneficial effects at the level of the mitochondrion

Skeletal muscle mitochondrial energetics are associated with maximal aerobic capacity and walking speed in older adults.

BACKGROUND: Lower ambulatory performance with aging may be related to a reduced oxidative capacity within skeletal muscle. This study examined the associations between skeletal muscle mitochondrial capacity and efficiency with walking performance in a group of older adults. METHODS: Thirty-seven older adults (mean age 78 years; 21 men and 16 women) completed an aerobic capacity (VO peak) test and measurement of preferred walking speed over 400 m. Maximal coupled (State 3; St3) mitochondrial respiration was determined by high-resolution respirometry in saponin-permeabilized myofibers obtained from percutanous biopsies of vastus lateralis (n = 22). Maximal phosphorylation capacity (ATP) of vastus lateralis was determined in vivo by P magnetic resonance spectroscopy (n = 30). Quadriceps contractile volume was determined by magnetic resonance imaging. Mitochondrial efficiency (max ATP production/max O consumption) was characterized using ATP per St3 respiration (ATP/St3). RESULTS: In vitro St3 respiration was significantly correlated with in vivo ATP (r = .47, p = .004). Total oxidative capacity of the quadriceps (St3*quadriceps contractile volume) was a determinant of VO peak (r = .33, p = .006). ATP (r = .158, p = .03) and VO peak (r = .475, p < .0001) were correlated with preferred walking speed. Inclusion of both ATP/St3 and VO peak in a multiple linear regression model improved the prediction of preferred walking speed (r = .647, p < .0001), suggesting that mitochondrial efficiency is an important determinant for preferred walking speed. CONCLUSIONS: Lower mitochondrial capacity and efficiency were both associated with slower walking speed within a group of older participants with a wide range of function. In addition to aerobic capacity, lower mitochondrial capacity and efficiency likely play roles in slowing gait speed with age

Skeletal muscle mitochondrial energetics are associated with maximal aerobic capacity and walking speed in older adults.

BACKGROUND: Lower ambulatory performance with aging may be related to a reduced oxidative capacity within skeletal muscle. This study examined the associations between skeletal muscle mitochondrial capacity and efficiency with walking performance in a group of older adults. METHODS: Thirty-seven older adults (mean age 78 years; 21 men and 16 women) completed an aerobic capacity (VO peak) test and measurement of preferred walking speed over 400 m. Maximal coupled (State 3; St3) mitochondrial respiration was determined by high-resolution respirometry in saponin-permeabilized myofibers obtained from percutanous biopsies of vastus lateralis (n = 22). Maximal phosphorylation capacity (ATP) of vastus lateralis was determined in vivo by P magnetic resonance spectroscopy (n = 30). Quadriceps contractile volume was determined by magnetic resonance imaging. Mitochondrial efficiency (max ATP production/max O consumption) was characterized using ATP per St3 respiration (ATP/St3). RESULTS: In vitro St3 respiration was significantly correlated with in vivo ATP (r = .47, p = .004). Total oxidative capacity of the quadriceps (St3*quadriceps contractile volume) was a determinant of VO peak (r = .33, p = .006). ATP (r = .158, p = .03) and VO peak (r = .475, p < .0001) were correlated with preferred walking speed. Inclusion of both ATP/St3 and VO peak in a multiple linear regression model improved the prediction of preferred walking speed (r = .647, p < .0001), suggesting that mitochondrial efficiency is an important determinant for preferred walking speed. CONCLUSIONS: Lower mitochondrial capacity and efficiency were both associated with slower walking speed within a group of older participants with a wide range of function. In addition to aerobic capacity, lower mitochondrial capacity and efficiency likely play roles in slowing gait speed with age

Skeletal muscle NAMPT is induced by exercise in humans

In mammals, nicotinamide phosphoribosyltransferase (NAMPT) is responsible for the first and rate-limiting step in the conversion of nicotinamide to nicotinamide adenine dinucleotide (NAD+). NAD+ is an obligate cosubstrate for mammalian sirtuin-1 (SIRT1), a deacetylase that activates peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), which in turn can activate mitochondrial biogenesis. Given that mitochondrial biogenesis is activated by exercise, we hypothesized that exercise would increase NAMPT expression, as a potential mechanism leading to increased mitochondrial content in muscle. A cross-sectional analysis of human subjects showed that athletes had about a twofold higher skeletal muscle NAMPT protein expression compared with sedentary obese, nonobese, and type 2 diabetic subjects (P < 0.05). NAMPT protein correlated with mitochondrial content as estimated by complex III protein content (R2 = 0.28, P < 0.01), MRS-measured maximal ATP synthesis (R2 = 0.37, P = 0.002), and V̇o2max (R2 = 0.63, P < 0.0001). In an exercise intervention study, NAMPT protein increased by 127% in sedentary nonobese subjects after 3 wk of exercise training (P < 0.01). Treatment of primary human myotubes with forskolin, a cAMP signaling pathway activator, resulted in an ∼2.5-fold increase in NAMPT protein expression, whereas treatment with ionomycin had no effect. Activation of AMPK via AICAR resulted in an ∼3.4-fold increase in NAMPT mRNA (P < 0.05) as well as modest increases in NAMPT protein (P < 0.05) and mitochondrial content (P < 0.05). These results demonstrate that exercise increases skeletal muscle NAMPT expression and that NAMPT correlates with mitochondrial content. Further studies are necessary to elucidate the pathways regulating NAMPT as well as its downstream effects

Oxygen uptake and blood metabolic responses to a 400-m run

This study aimed to investigate the oxygen uptake and metabolic responses during a 400-m run reproducing the pacing strategy used in competition. A portable gas analyser was used to measure the oxygen uptake (V ˙ O 2 ) of ten specifically trained runners racing on an outdoor track. The tests included (1) an incremental test to determine maximal V ˙ O 2 (V ˙ O 2max ) and the velocity associated with V ˙ O 2max (v−V ˙ O 2max ), (2) a maximal 400-m (400T) and 3) a 300-m running test (300T) reproducing the exact pacing pattern of the 400T. Blood lactate, bicarbonate concentrations [HCO − 3 ], pH and arterial oxygen saturation were analysed at rest and 1, 4, 7, 10 min after the end of the 400 and 300T. The peak V ˙ O 2 recorded during the 400T corresponded to 93.9 ± 3.9% of V ˙ O 2max and was reached at 24.4 ± 3.2 s (192 ± 22 m). A significant decrease in V ˙ O 2 (P < 0.05) was observed in all subjects during the last 100 m, although the velocity did not decrease below v−V ˙ O 2max . The V ˙ O 2 in the last 5 s was correlated with the pH (r = 0.86, P < 0.0005) and [HCO − 3 ] (r = 0.70, P < 0.05) measured at the end of 300T. Additionally, the velocity decrease observed in the last 100 m was inversely correlated with [HCO − 3 ] and pH at 300T (r = −0.83, P < 0.001, r = −0.69, P < 0.05, respectively). These track running data demonstrate that acidosis at 300 m was related to both the V ˙ O 2 response and the velocity decrease during the final 100 m of a 400-m run