Explore the vast range of titles available.

Prolonged immobilization of the human body results in functional impairments and musculoskeletal system deconditioning that may be attenuated by adequate muscle exercise. In a 56-day horizontal bed rest campaign involving voluntary males we investigated the effects of vibration muscle exercise (RVE, 2x6 min daily) on the lower limb skeletal muscles using a newly designed foot plantar trainer (Galileo Space) for use at supine position during bed rest. The maximally voluntary isometric plantar flexion force was maintained following regular RVE bouts during bed rest (controls -18.6 %, P<0.05). At the start (BR2) and end of bed rest (BR55) muscle biopsies were taken from both mixed fast/slow-type vastus lateralis (VL) and mainly slow-type soleus muscle (SOL), each having n=10. RVE group: the size of myofiber types I and II was largely unchanged in VL, and increased in SOL. Ctrl group: the SOL depicted a disrupted pattern of myofibers I/II profiles (i.e., type II>140 % vs. preBR) suggesting a slow-to-fast muscle phenotype shift. In RVE-trained SOL, however, an overall conserved myofiber I/II pattern was documented. RVE training increased the activity-dependent expression of nitric oxide synthase type 1 immunofluorescence at SOL and VL myofiber membranes. These data provide evidence for the beneficial effects of RVE training on the deconditioned structure and function of the lower limb skeletal muscle. Daily short RVE should be employed as an effective atrophy countermeasure co-protocol preferentially addressing postural calf muscles during prolonged clinical immobilization or long-term human space missions.

Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by CAG trinucleotide expansion in the gene encoding the androgen receptor (AR). In the central nervous system, lower motor neurons are selectively affected, whereas pathology of patients and animal models also indicates involvement of skeletal muscle including loss of fast-twitch type 2 fibres and increased slow-twitch type 1 fibres, together with a glycolytic-to-oxidative metabolic switch. Evaluation of muscle and fat using MRI, in addition to biochemical indices such as serum creatinine level, are promising biomarkers to track the disease progression. The serum level of creatinine starts to decrease before the onset of muscle weakness, followed by the emergence of hand tremor, a prodromal sign of the disease. Androgen-dependent nuclear accumulation of the polyglutamine-expanded AR is an essential step in the pathogenesis, providing therapeutic opportunities via hormonal manipulation and gene silencing with antisense oligonucleotides. Animal studies also suggest that hyperactivation of Src, alteration of autophagy and a mitochondrial deficit underlie the neuromuscular degeneration in SBMA and provide alternative therapeutic targets.

Summary Aging is associated with the development of insulin resistance, increased adiposity, and accumulation of ectopic lipid deposits in tissues and organs. Starting in mid‐life there is a progressive decline in lean muscle mass associated with the preferential loss of glycolytic, fast‐twitch myofibers. However, it is not known to what extent muscle loss and metabolic dysfunction are causally related or whether they are independent epiphenomena of the aging process. Here, we utilized a skeletal‐muscle‐specific, conditional transgenic mouse expressing a constitutively active form of Akt1 to examine the consequences of glycolytic, fast‐twitch muscle growth in young vs. middle‐aged animals fed standard low‐fat chow diets. Activation of the Akt1 transgene led to selective skeletal muscle hypertrophy, reversing the loss of lean muscle mass observed upon aging. The Akt1‐mediated increase in muscle mass led to reductions in fat mass and hepatic steatosis in older animals, and corrected age‐associated impairments in glucose metabolism. These results indicate that the loss of lean muscle mass is a significant contributor to the development of age‐related metabolic dysfunction and that interventions that preserve or restore fast/glycolytic muscle may delay the onset of metabolic disease.

Significance Folliculin interacting protein-1 (Fnip1) is an intracellular protein known to interact with folliculin (a protein mutated in Birt Hogg Dube’ Syndrome) and the master metabolic sensor AMP kinase. However, the roles of Fnip1 in mammalian development and function are unclear. In this study, we used mice deficient in Fnip1 to show that Fnip1 regulates skeletal muscle fiber type specification. Mice deficient in Fnip1 were significantly enriched for highly oxidative skeletal muscle that is more resistant to fatigue than wild-type muscle. Loss of Fnip1 also decreased muscle damage in a mouse model of Duchenne muscular dystrophy. These results reveal a previously unidentified function for Fnip1 and suggest that pharmacological inhibition of Fnip1 may reduce muscle damage in patients with muscular dystrophy. Mammalian skeletal muscle is broadly characterized by the presence of two distinct categories of muscle fibers called type I “red” slow twitch and type II “white” fast twitch, which display marked differences in contraction strength, metabolic strategies, and susceptibility to fatigue. The relative representation of each fiber type can have major influences on susceptibility to obesity, diabetes, and muscular dystrophies. However, the molecular factors controlling fiber type specification remain incompletely defined. In this study, we describe the control of fiber type specification and susceptibility to metabolic disease by folliculin interacting protein-1 (Fnip1). Using Fnip1 null mice, we found that loss of Fnip1 increased the representation of type I fibers characterized by increased myoglobin, slow twitch markers [myosin heavy chain 7 (MyH7), succinate dehydrogenase, troponin I 1, troponin C1, troponin T1], capillary density, and mitochondria number. Cultured Fnip1 -null muscle fibers had higher oxidative capacity, and isolated Fnip1 -null skeletal muscles were more resistant to postcontraction fatigue relative to WT skeletal muscles. Biochemical analyses revealed increased activation of the metabolic sensor AMP kinase (AMPK), and increased expression of the AMPK-target and transcriptional coactivator PGC1α in Fnip1 null skeletal muscle. Genetic disruption of PGC1α rescued normal levels of type I fiber markers MyH7 and myoglobin in Fnip1 -null mice. Remarkably, loss of Fnip1 profoundly mitigated muscle damage in a murine model of Duchenne muscular dystrophy. These results indicate that Fnip1 controls skeletal muscle fiber type specification and warrant further study to determine whether inhibition of Fnip1 has therapeutic potential in muscular dystrophy diseases.

Age‐related loss of muscle mass and function is underpinned by changes at the myocellular level. However, our understanding of the aged muscle phenotype might be confounded by factors secondary to ageing per se, such as inactivity and adiposity. Here, using healthy, lean, recreationally active, older men, we investigated the impact of ageing on myocellular properties in skeletal muscle. Muscle biopsies were obtained from young men (22 ± 3 years, n = 10) and older men (69 ± 3 years, n = 11) matched for health status, activity level and body mass index. Immunofluorescence was used to assess myofibre composition, morphology (size and shape), capillarization, the content of satellite cells and myonuclei, the spatial relationship between satellite cells and capillaries, denervation and myofibre grouping. Compared with young muscle, aged muscle contained 53% more type I myofibres, in addition to smaller (−32%) and misshapen (3%) type II myofibres (P < 0.05). Aged muscle manifested fewer capillaries (−29%) and satellite cells (−38%) surrounding type II myofibres (P < 0.05); however, the spatial relationship between these two remained intact. The proportion of denervated myofibres was ∼2.6‐fold higher in old than young muscle (P < 0.05). Aged muscle had more grouped type I myofibres (∼18‐fold), primarily driven by increased size of existing groups rather than increased group frequency (P < 0.05). Aged muscle displayed selective deterioration of type II myofibres alongside increased denervation and myofibre grouping. These data are key to understanding the cellular basis of age‐related muscle decline and reveal a pressing need to fine‐tune strategies to preserve type II myofibres and innervation status in ageing populations. What is the central question of this study? How does ageing impact type I and type II myofibre properties in human muscle? What are the main findings and their importance? Type II myofibres in healthy, recreationally active, older adults were smaller, misshapen, and had fewer satellite cells and capillaries in comparison to young adults. Older adults also manifested an increased proportion of denervated and grouped myofibres. Our data suggest that age‐related changes in skeletal muscle are highly confined to type II myofibres. These observations are key to understanding how ageing impacts skeletal muscle in the absence of inactivity, adiposity and medications.

Background Adequate muscle fibre perfusion is critical for the maintenance of muscle mass; it is essential in the rapid delivery of oxygen, nutrients and growth factors to the muscle, stimulating muscle fibre growth. Muscle fibre capillarization is known to decrease substantially with advancing age. However, whether (relative) low muscle fibre capillarization negatively impacts the muscle hypertrophic response following resistance exercise training in older adults is unknown. Methods Twenty‐two healthy older men (71 ± 1 years) performed 24 weeks of progressive resistance type exercise training. To assess the change in muscle fibre characteristics, percutaneous biopsies from the vastus lateralis muscle were taken before and following 12 and 24 weeks of the intervention programme. A comparison was made between participants who had a relatively low type II muscle fibre capillary‐to‐fibre perimeter exchange index (CFPE; LOW group) and high type II muscle fibre CFPE (HIGH group) at baseline. Type I and type II muscle fibre size, satellite cell, capillary content and distance between satellite cells to the nearest capillary were determined by immunohistochemistry. Results Overall, type II muscle fibre size (from 5150 ± 234 to 6719 ± 446 µm2, P < 0.05) and satellite cell content (from 0.058 ± 0.006 to 0.090 ± 0.010 satellite cells per muscle fibre, P < 0.05) had increased significantly in response to 24 weeks of resistance exercise training. However, these improvements where mainly driven by differences in baseline type II muscle fibre capillarization, whereas muscle fibre size (from 5170 ± 390 to 7133 ± 314 µm2, P < 0.05) and satellite cell content (from 0.059 ± 0.009 to 0.102 ± 0.017 satellite cells per muscle fibre, P < 0.05) increased significantly in the HIGH group, no significant changes were observed in LOW group following exercise training. No significant changes in type I and type II muscle fibre capillarization were observed in response to 12 and 24 weeks of resistance exercise training in both the LOW and HIGH group. Conclusions Type II muscle fibre capillarization at baseline may be a critical factor for allowing muscle fibre hypertrophy to occur during prolonged resistance exercise training in older men.

Increased utrophin expression is known to reduce pathology in dystrophin-deficient skeletal muscles. Transgenic over-expression of PGC-1α has been shown to increase levels of utrophin mRNA and improve the histology of mdx muscles. Other reports have shown that PGC-1α signaling can lead to increased oxidative capacity and a fast to slow fiber type shift. Given that it has been shown that slow fibers produce and maintain more utrophin than fast skeletal muscle fibers, we hypothesized that over-expression of PGC-1α in post-natal mdx mice would increase utrophin levels via a fiber type shift, resulting in more slow, oxidative fibers that are also more resistant to contraction-induced damage. To test this hypothesis, neonatal mdx mice were injected with recombinant adeno-associated virus (AAV) driving expression of PGC-1α. PGC-1α over-expression resulted in increased utrophin and type I myosin heavy chain expression as well as elevated mitochondrial protein expression. Muscles were shown to be more resistant to contraction-induced damage and more fatigue resistant. Sirt-1 was increased while p38 activation and NRF-1 were reduced in PGC-1α over-expressing muscle when compared to control. We also evaluated if the use a pharmacological PGC-1α pathway activator, resveratrol, could drive the same physiological changes. Resveratrol administration (100 mg/kg/day) resulted in improved fatigue resistance, but did not achieve significant increases in utrophin expression. These data suggest that the PGC-1α pathway is a potential target for therapeutic intervention in dystrophic skeletal muscle.

OBJECTIVE:--We investigated whether alterations of glycolytic and oxidative enzyme capacity in skeletal muscle of patients with type 2 diabetes pertain to specific muscle fibers and are associated with changes in muscle fiber composition. RESEARCH DESIGN AND METHODS--Vastus lateralis muscle was obtained by percutaneous biopsy from 10 patients with type 2 diabetes and 15 age- and BMI-matched healthy volunteers. Using cytophotometry, muscle fiber composition and fiber type-specific glycolytic and oxidative enzyme activities were measured in slow oxidative, fast oxidative glycolytic, and fast glycolytic fibers. RESULTS:--In the whole muscle, oxidative activity was decreased in patients with type 2 diabetes. The slow oxidative fiber fraction was reduced by 16%, whereas the fast glycolytic fiber fraction was increased by 49% in skeletal muscle from the diabetic patients. Both oxidative and glycolytic enzyme activities were significantly increased in fast glycolytic and fast oxidative glycolytic fibers of type 2 diabetic patients. However, the fiber-specific ratio of glycolytic enzyme activity relative to oxidative activity was not different between type 2 diabetic patients and the control subjects. The myofibrillic ATP activity was significantly lower in all fiber types of patients with type 2 diabetes and correlates with glucose infusion rate during the steady state of a euglycemic-hyperinsulinemic clamp and maximal aerobic capacity and negatively with HbA[subscript 1c] values. CONCLUSIONS:--Reduced oxidative enzyme activity in muscle of type 2 diabetic patients is most likely due to a reduction in slow oxidative fibers. Increased glycolytic and oxidative enzyme activities in individual muscle fibers are closely related to measures of long-term glycemic control and whole-body insulin sensitivity and could therefore represent a compensatory mechanism of the muscle in function of the altered glucose metabolism.

Reasons for the progressive age-related loss of skeletal muscle mass and function, namely sarcopenia, are complex. Few studies describe sarcopenia in mice, although this species is the mammalian model of choice for genetic intervention and development of pharmaceutical interventions for muscle degeneration. One factor, important to sarcopenia-associated neuromuscular change, is myofibre denervation. Here we describe the morphology of the neuromuscular compartment in young (3 month) compared to geriatric (29 month) old female C57Bl/6J mice. There was no significant difference in the size or number of motoneuron cell bodies at the lumbar level (L1-L5) of the spinal cord at 3 and 29 months. However, in geriatric mice, there was a striking increase (by ∼2.5 fold) in the percentage of fully denervated neuromuscular junctions (NMJs) and associated deterioration of Schwann cells in fast extensor digitorum longus (EDL), but not in slow soleus muscles. There were also distinct changes in myofibre composition of lower limb muscles (tibialis anterior (TA) and soleus) with a shift at 29 months to a faster phenotype in fast TA muscle and to a slower phenotype in slow soleus muscle. Overall, we demonstrate complex changes at the NMJ and muscle levels in geriatric mice that occur despite the maintenance of motoneuron cell bodies in the spinal cord. The challenge is to identify which components of the neuromuscular system are primarily responsible for the marked changes within the NMJ and muscle, in order to selectively target future interventions to reduce sarcopenia.

Eccentric contraction (ECC) has been shown to induce leukocyte invasion into skeletal muscle, resulting in muscle inflammation. This study aimed to investigate whether prior ingestion of L-arginine (ARG), a nitric oxide precursor, inhibits ECC-induced macrophage invasion. Male Wistar rats received ARG in water for 7 days, beginning 3 days prior to ECC. ECCs were induced in the anterior crural muscles for 200 cycles. Three days later, the tibialis anterior and extensor digitorum longus muscles were excised for biochemical analysis and force measurement, respectively. ARG ingestion increased nitrite and nitrate levels in plasma and muscle, inhibiting force depression and reducing CD68 content in muscles subjected to ECC. ARG ingestion also ameliorated an ECC-induced increase in protein nitration, although neither ARG ingestion nor ECC induction affected protein carbonyl levels. The present results suggest that ingestion of ARG or ARG-rich foods may alleviate inflammation by attenuating phagocyte invasion in eccentrically contracted skeletal muscles.