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Increased CaVbeta1A expression with aging contributes to skeletal muscle weakness.

ABSTRACT: Ca2+ release from the sarcoplasmic reticulum (SR) into the cytosol is a crucial part of excitation-contraction (E-C) coupling. Excitation-contraction uncoupling, a deficit in Ca2+ release from the SR, is thought to be responsible for at least some of the loss in specific force observed in aging skeletal muscle. Excitation-contraction uncoupling may be caused by alterations in expression of the voltage-dependent calcium channel alpha1s (CaV1.1) and beta1a (CaVbeta1a) subunits, both of which are necessary for E-C coupling to occur. While previous studies have found CaV1.1 expression declines in old rodents, CaVbeta1a expression has not been previously examined in aging models. Western blot analysis shows a substantial increase of CaVbeta1a expression over the full lifespan of Friend Virus B (FVB) mice. To examine the specific effects of CaVbeta1a overexpression, a CaVbeta1a-YFP plasmid was electroporated in vivo into young animals. The resulting increase in expression of CaVbeta1a corresponded to decline of CaV1.1 over the same time period. YFP fluorescence, used as a measure of CaVbeta1a-YFP expression in individual fibers, also showed an inverse relationship with charge movement, measured using the whole-cell patch-clamp technique. Specific force was significantly reduced in young CaVbeta1a-YFP electroporated muscle fibers compared with sham-electroporated, age-matched controls. siRNA interference of CaVbeta1a in young muscles reduced charge movement, while charge movement in old was restored to young control levels. These studies imply CaVbeta1a serves as both a positive and negative regulator CaV1.1 expression, and that endogenous overexpression of CaVbeta1a during old age may play a role in the loss of specific force.

SUBMITTER: Taylor JR

PROVIDER: S-EPMC2765867 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Increased CaVbeta1A expression with aging contributes to skeletal muscle weakness.

Taylor Jackson R JR Zheng Zhenlin Z Wang Zhong-Min ZM Payne Anthony M AM Messi María L ML Delbono Osvaldo O

Aging cell 20090805 5

Ca2+ release from the sarcoplasmic reticulum (SR) into the cytosol is a crucial part of excitation-contraction (E-C) coupling. Excitation-contraction uncoupling, a deficit in Ca2+ release from the SR, is thought to be responsible for at least some of the loss in specific force observed in aging skeletal muscle. Excitation-contraction uncoupling may be caused by alterations in expression of the voltage-dependent calcium channel alpha1s (CaV1.1) and beta1a (CaVbeta1a) subunits, both of which are n ...[more]

PMID: 19663902

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Project description:BackgroundMuscle weakness is a common symptom in numerous diseases and a regularly occurring problem associated with ageing. Prolonged low-frequency force depression (PLFFD) is a form of exercise-induced skeletal muscle weakness observed after exercise. Three different intramuscular mechanisms underlying PLFFD have been identified: decreased sarcoplasmic reticulum Ca2+ release, decreased myofibrillar Ca2+ sensitivity, and myofibrillar dysfunction. We here used these three forms of PLFFD as models to study the effectiveness of a fast skeletal muscle troponin activator, CK-2066260, to mitigate muscle weakness.MethodsExperiments were performed on intact single muscle fibres or fibre bundles from mouse flexor digitorum brevis, which were stimulated with electrical current pulses, while force and the free cytosolic [Ca2+ ] ([Ca2+ ]i ) were measured. PLFFD was induced by three different stimulation protocols: (i) repeated isometric contractions at low intensity (350 ms tetani given every 5 s for 100 contractions); (ii) repeated isometric contractions at high intensity (250 ms tetani given every 0.5 s for 300 contractions); and (iii) repeated eccentric contractions (350 ms tetani with 20% length increase given every 20 s for 10 contractions). The extent and cause of PLFFD were assessed by comparing the force-[Ca2+ ]i relationship at low (30 Hz) and high (120 Hz) stimulation frequencies before (control) and 30 min after induction of PLFFD, and after an additional 5 min of rest in the presence of CK-2066260 (10 μM).ResultsProlonged low-frequency force depression following low-intensity and high-intensity fatiguing contractions was predominantly due to decreased sarcoplasmic reticulum Ca2+ release and decreased myofibrillar Ca2+ sensitivity, respectively. CK-2066260 exposure resulted in marked increases in 30 Hz force from 52 ± 16% to 151 ± 13% and from 6 ± 4% to 98 ± 40% of controls with low-intensity and high-intensity contractions, respectively. Following repeated eccentric contractions, PLFFD was mainly due to myofibrillar dysfunction, and it was not fully reversed by CK-2066260 with 30 Hz force increasing from 48 ± 8% to 76 ± 6% of the control.ConclusionsThe fast skeletal muscle troponin activator CK-2066260 effectively mitigates muscle weakness, especially when it is caused by impaired activation of the myofibrillar contractile machinery due to either decreased sarcoplasmic reticulum Ca2+ release or reduced myofibrillar Ca2+ sensitivity.

Project description:ObjectiveTo investigate the effects of a 16-week concurrent exercise regimen [resistance exercise (RE) + functional exercise (FE)] in combination with, or without, a leucine-enriched whey protein isolate supplement on muscle strength, physical functioning, aerobic capacity, and cardiometabolic health in older adults (≥60 years). Physical activity levels were also evaluated 6 months post-cessation of the intervention.MethodsForty-six, community-dwelling, previously untrained males, and females [age: 68 ± 5 years (mean ± SD); BMI: 27.8 ± 6.2 kg/m2] who completed the trial were initially randomized to one of two independent arms [Exercise n = 24 (E); Exercise+Protein n = 22 (EP)]. Both arms completed 16 weeks of RE (performed to fatigue) (2 times/week) with FE (1 time/week) on non-consecutive days. Additionally, EP were administered a leucine-enriched whey protein supplement (3 times/day) for 16 weeks based on individual body-weight (1.5 g/kg/day).ResultsAs a result of dietary supplementation, protein intake increased in EP (∼1.2 ± 0.4 to 1.5 ± 0.7 g/kg/day) during the intervention. Maximal strength (1RM) values for leg press (E: +39 ± 7 kg, p = 0.006; EP: +63 ± 7 kg, p < 0.001), chest press (E: +22 ± 4 kg, p < 0.001; EP: +21 ± 6 kg, p < 0.001), and bicep curl (E: +7 ± 0 kg, p = 0.002; EP: +6 ± 1 kg, p = 0.008) significantly increased in E and EP respectively, with no differences between arms (p > 0.05). Physical functioning in the obstacle course (E: -5.1 ± 6.8 s, p < 0.001; EP: -2.8 ± 0.8 s, p < 0.001) and short-physical performance battery scores (E: +0.5 ± 0.5, p = <0.001; EP: +0.4 ± 0.5, p = 0.038), and aerobic capacity in the 6-min walk test (E: +37 ± 24 m, p = 0.014; EP: +36 ± 3 m, p = 0.005) improved in E and EP respectively, with no differences between arms (p > 0.05). No significant change was observed for markers of cardiometabolic health (glycaemic control or blood pressure) (p > 0.05). At follow-up, 86% of older adults reported to performing physical activity ≥1 per week. Of those, 61% were still participating in strength- and cardiovascular- based exercise.ConclusionConcurrent exercise (RE + FE) offers a potent method to combat age-related muscle weakness, and our results suggest a high proportion of older adults may continue to exercise unsupervised. However, leucine-enriched whey protein isolate supplementation did not confer any additional benefit in those already consuming ample amounts of dietary protein at trial enrolment. Future trials should utilize a whole-foods approach and investigate the effects in frail and non-frail older adults habitually consuming the RDA of protein, to assess if a higher intake of protein is needed to delay the onset of muscle weakness.Trial registrationClinicaltrials.gov Identifier: NCT02912130.

Project description:Background & aimsMetabolic characterization of a well-defined group of patients could be a powerful tool in revealing metabolic signatures to explain limb muscle weakness in chronic diseases. Studies are currently limited in Chronic Obstructive Pulmonary Disease (COPD) to the identification of differential amino acid concentrations but lack comprehensive analysis of the flux through relevant muscle function related metabolic pathways.MethodsIn 23 stable patients with moderate to very severe COPD and 19 healthy controls, a comprehensive metabolic flux analysis was conducted by administering an intravenous pulse and primed constant infusion of multiple stable tracers of amino acids known to play a role in muscle health. Blood samples were obtained to calculate production (WBP) and interconversion rates, and plasma concentrations of these amino acids. Lower and upper limb muscle strength, muscle mass, lung function, physical activity level, and disease history and characteristics were assessed.ResultsThe COPD group was characterized by lower and upper limb muscle weakness (P < 0.01) despite preserved muscle mass. Higher values were found in COPD for plasma glutamine, WBP of leucine (P < 0.001), 3-methylhistidine (P < 0.01) (marker of enhanced myofibrillar protein breakdown), citrulline (P < 0.05), and arginine to citrulline conversion (P < 0.05) (reflecting enhanced nitric oxide synthesis). Plasma concentration of β-hydroxy β-methylbutyrate (HMB with anticatabolic, anabolic and contractile properties), WBP of glycine (precursor of creatine and glutathione), and transcutaneous O2 saturation explained up to 79% and 65% of the variation in strength of the lower and upper limb muscles, respectively, in COPD.ConclusionsComprehensive metabolic flux analysis revealed a homogenous metabolic signature in stable patients with COPD and a specific metabolic profile in those with skeletal muscle weakness.Clinical trial registryClinicalTrials.gov; No. NCT01787682; URL: www.clinicaltrials.gov.

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Increased CaVbeta1A expression with aging contributes to skeletal muscle weakness.

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Increased CaVbeta1A expression with aging contributes to skeletal muscle weakness.

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