Exercise intolerance and rapid skeletal muscle energetic decline in human age-associated frailty

Lewsey, Sabra C.; Weiss, Kilian; Schär, Michael; Zhang, Yi; Bottomley, Paul A.; Samuel, T. Jake; Qin, Xue; Steinberg, Angela; Walston, Jeremy D.; Gerstenblith, Gary; Weiss, Robert G.

doi:10.1172/jci.insight.141246

Cited by 34 publications

(39 citation statements)

References 66 publications

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“…The HF cohort in this study was significantly older than the control cohort, with a mean age difference of 20 years. In addition, normal aging induces a shift in skeletal muscle metabolism in the form of sarcopenia 37 , 38 , the effect of which may be a contributor to the results seen here given the age difference between the cohorts. Increasing age of the HF cohort increases the likelihood of multiple co-morbidities including hypertension and coronary heart disease.…”

Section: Discussionmentioning

confidence: 81%

Dynamic 31P-MRI and 31P-MRS of lower leg muscles in heart failure patients

Menon

Xia

Katz

et al. 2021

Sci Rep

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Impaired oxidative metabolism is one of multi-variate factors leading to exercise intolerance in heart failure patients. The purpose of the study was to demonstrate the use of dynamic 31P magnetic resonance spectroscopy (MRS) and 31P magnetic resonance imaging (MRI) techniques to measure PCr resynthesis rate post-exercise as a biomarker for oxidative metabolism in skeletal muscle in HF patients and controls. In this prospective imaging study, we recruited six HF patients and five healthy controls. The imaging protocol included 31P-MRS, spectrally selective 3D turbo spin echo for 31P-MRI, and Dixon multi-echo GRE for fat–water imaging on a 3 T clinical MRI scanner. All the subjects were scanned pre-exercise, during plantar flexion exercise, and post-exercise recovery, with two rounds of exercise for 31P -MRS and 31P-MRI, respectively. Unpaired t-tests were used to compare 31P-MRS and 31P-MRI results between the HF and control cohorts. The results show that PCr resynthesis rate was significantly slower in the HF cohort compared to the controls using 31P-MRS (P = 0.0003) and 31P-MRI (P = 0.0014). 31P-MRI showed significant differences between the cohorts in muscle groups (soleus (P = 0.0018), gastrocnemius lateral (P = 0.0007) and gastrocnemius medial (P = 0.0054)). The results from this study suggest that 31P-MRS/31P-MRI may be used to quantify lower leg muscle oxidative metabolism in HF patients, with 31P-MRI giving an additional advantage of allowing further localization of oxidative metabolism deficits. Upon further validation, these techniques may serve as a potentially useful clinical imaging biomarker for staging and monitoring therapies in HF-patients.

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Section: Discussionmentioning

confidence: 81%

Dynamic 31P-MRI and 31P-MRS of lower leg muscles in heart failure patients

Menon

Xia

Katz

et al. 2021

Sci Rep

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“…Thus, the frail and prefrail groups had PCr recovery that was 57 and 20 seconds slower, respectively, than for the nonfrail group. A recently published study shows rapid energetic decline in the exercised skeletal muscle of frail compared to nonfrail older adults, further demonstrating stress-induced energy dysfunction in frailty 51 . Stress-response system, HPA axis.…”

Section: Physical Frailty Is An Emergent State Of a Compromised Complmentioning

confidence: 89%

“…Evidence of mitochondrial energy production deficits exists in both humans and a mouse model of frailty 28,84 . In humans, PCr recovery time, a measure of mitochondrial oxidative phosphorylation, is reduced 50,51 . In a mouse model of frailty derived through chronic inflammation, skeletal muscle ATP kinetics are impaired and decreased mitochondrial degradation in skeletal muscle has been identified 28,85 .…”

Section: Potential Drivers Of the Complex System Dysregulation Underlmentioning

confidence: 99%

“…In a mouse model of frailty derived through chronic inflammation, skeletal muscle ATP kinetics are impaired and decreased mitochondrial degradation in skeletal muscle has been identified 28,85 . Finally, indirect evidence comes from studies demonstrating that mitochondrial dysfunction is highly related to glucose intolerance at a tissue level 86 , which is associated in humans with physical frailty 21,51 .…”

Section: Potential Drivers Of the Complex System Dysregulation Underlmentioning

confidence: 99%

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The physical frailty syndrome as a transition from homeostatic symphony to cacophony

et al. 2021

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W hy do some older people die in the face of heatwaves and others do not? What has created the heightened risk of mortality from COVID-19 in older people? This vulnerability comes in part from the effects of chronic diseases and other health-related conditions that accumulate with increasing age. We hypothesize that it also results from what clinicians term 'frailty' , a state of depleted reserve resulting in increased vulnerability to stressors that emerges during aging independently of any specific disease. Definitions of frailty are abound. The two dominantly used are 'phenotypic frailty' , where a validated clinical presentation marks a distinct clinical syndrome and pathophysiology 1,2 , and a 'deficit accumulation model' frailty index, which summarizes the presence of multiple clinically identified diseases, their clinical and laboratory manifestations and consequences, and risk factors into a composite index for risk prediction 3,4. These two distinct conceptualizations both carry the same nomenclature and both predict high mortality and institutionalization risk, but they denote different theory, etiologies, measures and possibly processes, and identify considerably different populations and different targets of intervention 5. Other definitions of frailty have integrated additional constructs, particularly cognitive frailty, as proposed by the International Association of Gerontology and Geriatrics/International Academy on Nutrition and Aging (IAGG/IANA) 6,7. However, such integration has the potential to obscure meaningful differences, as exemplified by the observation that 22% of people with Alzheimer's disease had no physical indicators of frailty 8. This is reinforced by clinical encounters with older adults who are physically robust but cognitively frail and vice versa. Accordingly, we view other types of frailty, whether they are cognitive, emotional or psychosocial frailty, as important but distinct constructs that can be most fruitfully measured separately from each other and from phenotypic frailty. Both phenotypically identified frailty and the frailty index, finally, also link to other constructs in gerontology, notably, 'allostasis' , 'homeostasis' , 'robustness' , 'reserve' and 'resilience'. A thorough disambiguation of these related concepts is beyond our scope, but provisional definitions are given in Box 1 and considered below. The syndrome of phenotypic frailty-henceforth termed 'physical frailty'-is the focus of this Perspective. Clinical presentation of the phenotype denotes a distinctive high-risk clinical state that indicates decreased reserves and high vulnerability to stressors. The state is clinically recognizable through the presence of three or more of five key clinical signs and symptoms: weakness, slow walking speed, low physical activity, fatigue or exhaustion, and unintentional weight loss (Fig. 1 and Box 1) 1,2. Prevalence in people 65 years and older varies across populations, with a predominant rate of 7-10% in community-dwelling older adults, which increases to over 25% ...

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“…The loss of skeletal muscle mass with aging, which is known as sarcopenia, diminishes muscle strength and exercise capacity, which seriously affects the quality of life of elderly people and is a major sign of age-associated frailty [ 1 , 2 ]. While regular physical exercise is the best and only way to maintain skeletal muscle mass, a recent study reported that exercise intolerance and rapid skeletal muscle energetic decline during exercise are characteristics of age-associated frailty [ 3 ], suggesting that when an elderly person begins to suffer from exercise intolerance, a vicious circle is started in which reduction in skeletal muscle mass leads to further deterioration of exercise intolerance. Increasing exercise endurance capacity by improving skeletal muscle energy metabolism is expected to be an effective means of breaking this vicious cycle.…”

Section: Introductionmentioning

confidence: 99%

Skeletal muscle-specific Keap1 disruption modulates fatty acid utilization and enhances exercise capacity in female mice

et al. 2021

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Skeletal muscle health is important for the prevention of various age-related diseases. The loss of skeletal muscle mass, which is known as sarcopenia, underlies physical disability, poor quality of life and chronic diseases in elderly people. The transcription factor NRF2 plays important roles in the regulation of the cellular defense against oxidative stress, as well as the metabolism and mitochondrial activity. To determine the contribution of skeletal muscle NRF2 to exercise capacity, we conducted skeletal muscle-specific inhibition of KEAP1, which is a negative regulator of NRF2, and examined the cell-autonomous and non-cell-autonomous effects of NRF2 pathway activation in skeletal muscles. We found that NRF2 activation in skeletal muscles increased slow oxidative muscle fiber type and improved exercise endurance capacity in female mice. We also observed that female mice with NRF2 pathway activation in their skeletal muscles exhibited enhanced exercise-induced mobilization and β-oxidation of fatty acids. These results indicate that NRF2 activation in skeletal muscles promotes communication with adipose tissues via humoral and/or neuronal signaling and facilitates the utilization of fatty acids as an energy source, resulting in increased mitochondrial activity and efficient energy production during exercise, which leads to improved exercise endurance.

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Exercise intolerance and rapid skeletal muscle energetic decline in human age-associated frailty

Cited by 34 publications

References 66 publications

Dynamic 31P-MRI and 31P-MRS of lower leg muscles in heart failure patients

Dynamic 31P-MRI and 31P-MRS of lower leg muscles in heart failure patients

The physical frailty syndrome as a transition from homeostatic symphony to cacophony

Skeletal muscle-specific Keap1 disruption modulates fatty acid utilization and enhances exercise capacity in female mice

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