Alterations in intrinsic mitochondrial function with aging are fiber type-specific and do not explain differential atrophy between muscles

To determine whether mitochondrial dysfunction is causally related to muscle atrophy with aging, we examined respiratory capacity, H(2) O(2) emission, and function of the mitochondrial permeability transition pore (mPTP) in permeabilized myofibers prepared from four rat muscles that span a range of fiber type and degree of age-related atrophy. Muscle atrophy with aging was greatest in fast-twitch gastrocnemius (Gas) muscle (-38%), intermediate in both the fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus (Sol) muscles (-21%), and non-existent in adductor longus (AL) muscle (+47%). In contrast, indices of mitochondrial dysfunction did not correspond to this differential degree of atrophy. Specifically, despite higher protein expression for oxidative phosphorylation (oxphos) system in fast Gas and EDL, state III respiratory capacity per myofiber wet weight was unchanged with aging, whereas the slow Sol showed proportional decreases in oxphos protein, citrate synthase activity, and state III respiration. Free radical leak (H(2) O(2) emission per O(2) flux) under state III respiration was higher with aging in the fast Gas, whereas state II free radical leak was higher in the slow AL. Only the fast muscles had impaired mPTP function with aging, with lower mitochondrial calcium retention capacity in EDL and shorter time to mPTP opening in Gas and EDL. Collectively, our results underscore that the age-related changes in muscle mitochondrial function depend largely upon fiber type and are unrelated to the severity of muscle atrophy, suggesting that intrinsic changes in mitochondrial function are unlikely to be causally involved in aging muscle atrophy.     

FGF19 protects skeletal muscle against obesity-induced muscle atrophy,metabolic derangement and abnormal irisin levels via the AMPK/SIRT-1/PGC-α pathway

Obesity is associated with biological dysfunction in skeletal muscle. As a condition of obesity accompanied by muscle mass loss and physical dysfunction, sarcopenic obesity (SO) has become a novel public health problem. Human fibroblast growth factor 19 (FGF19) plays a therapeutic role in metabolic diseases. However, the protective effects of FGF19 on skeletal muscle in obesity and SO are still not completely understood. Our results showed that FGF19 administration improved muscle loss and grip strength in young and aged mice fed a high-fat diet (HFD). Increases in muscle atrophy markers (FOXO-3, Atrogin-1, MuRF-1) were abrogated by FGF19 in palmitic acid (PA)-treated C2C12 myotubes and in the skeletal muscle of HFD-fed mice. FGF19 not only reduced HFD-induced body weight gain, excessive lipid accumulation and hyperlipidaemia but also promoted energy expenditure (PGC-1α, UCP-1, PPAR-γ) in brown adipose tissue (BAT). FGF19 treatment restored PA- and HFD-induced hyperglycaemia, impaired glucose tolerance and insulin resistance (IRS-1, GLUT-4) and mitigated the PA- and HFD-induced decrease in FNDC-5/irisin expression. However, these beneficial effects of FGF19 on skeletal muscle were abolished by inhibiting AMPK, SIRT-1 and PGC-1α expression. Taken together, this study suggests that FGF19 protects skeletal muscle against obesity-induced muscle atrophy, metabolic derangement and abnormal irisin secretion partially through the AMPK/SIRT-1/PGC-α signalling pathway, which might be a potential therapeutic target for obesity and SO.     

Variations in the age and growth of yellowfin tuna larvae,Thunnus albacares,collected about the Mississippi River plume

Synopsis Eight hundred and one yellowfin tuna larvae ranging from 2.57–7.48 mm SL were collected near the Mississippi River discharge plume in the Gulf of Mexico during July and September, 1987. Larvae were most abundant at intermediate salinities (i.e. frontal waters) where chlorophylla and macrozooplankton displacement values were also highest. Using sagittal otolith microstructure, we estimated larval ages ranging from 3–14 d. These ages were used to back calculate spawning dates from 13–24 July and 22–31 August. Mean absolute individual growth rate (length age^–1) was 0.47 mm d^–1, with the least squares linear regression SL = 1.67 + 0.47 AGE (r² = 0.60, Pr> F = 0.0001) representing the best growth curve. Highest growth occurred at intermediate salinities near 31%, and temperatures near 29° C. There was significant temporal variation in growth, with larvae collected in July growing slower than those from September (0.37 and 0.48 mm d^–1, respectively). The pooled instantaneous daily mortality rate (Z) of the larvae was estimated to be 0.33 d^–1 (0.16 d^–1 in July and 0.41 d^–1 in September). These results show that significant spawning of yellowfin tuna may occur in the northern Gulf of Mexico in the vicinity of the Mississippi River discharge plume, and suggest that larval growth and survival may be enhanced in the plume frontal waters.     

Age‐related changes in miR‐143‐3p:Igfbp5 interactions affect muscle regeneration

A common characteristic of aging is defective regeneration of skeletal muscle. The molecular pathways underlying age‐related decline in muscle regenerative potential remain elusive. microRNAs are novel gene regulators controlling development and homeostasis and the regeneration of most tissues, including skeletal muscle. Here, we use satellite cells and primary myoblasts from mice and humans and an in vitro regeneration model, to show that disrupted expression of microRNA‐143‐3p and its target gene, Igfbp5, plays an important role in muscle regeneration in vitro. We identified miR‐143 as a regulator of the insulin growth factor‐binding protein 5 (Igfbp5) in primary myoblasts and show that the expression of miR‐143 and its target gene is disrupted in satellite cells from old mice. Moreover, we show that downregulation of miR‐143 during aging may act as a compensatory mechanism aiming at improving myogenesis efficiency; however, concomitant upregulation of miR‐143 target gene, Igfbp5, is associated with increased cell senescence, thus affecting myogenesis. Our data demonstrate that dysregulation of miR‐143‐3p:Igfbp5 interactions in satellite cells with age may be responsible for age‐related changes in satellite cell function.     

Mitochondrial functional impairment with aging is exaggerated in isolated mitochondria compared to permeabilized myofibers

Mitochondria regulate cellular bioenergetics and apoptosis and have been implicated in aging. However, it remains unclear whether age‐related loss of muscle mass, known as sarcopenia, is associated with abnormal mitochondrial function. Two technically different approaches have mainly been used to measure mitochondrial function: isolated mitochondria and permeabilized myofiber bundles, but the reliability of these measures in the context of sarcopenia has not been systematically assessed before. A key difference between these approaches is that contrary to isolated mitochondria, permeabilized bundles contain the totality of fiber mitochondria where normal mitochondrial morphology and intracellular interactions are preserved. Using the gastrocnemius muscle from young adult and senescent rats, we show marked effects of aging on three primary indices of mitochondrial function (respiration, H₂O₂ emission, sensitivity of permeability transition pore to Ca²⁺) when measured in isolated mitochondria, but to a much lesser degree when measured in permeabilized bundles. Our results clearly demonstrate that mitochondrial isolation procedures typically employed to study aged muscles expose functional impairments not seen in situ. We conclude that aging is associated with more modest changes in mitochondrial function in sarcopenic muscle than suggested previously from isolated organelle studies.