Result

The transcription coactivator known as peroxisome proliferator-activated receptor-

gamma coactivator (PGC)-1alpha is an important component in the control of cellular energy

metabolism. It is a member of the family of peroxisome proliferator-activated receptor-gamma

coactivators. It is significantly stimulated by exposure to cold, connecting this environmental

stimulation to adaptive thermogenesis.PGC-1alpha is involved in the control of both

carbohydrate and lipid metabolism, as well as the stimulation of mitochondrial biogenesis and

the promotion of the remodelling of muscle tissue to a fiber-type composition that is biologically

more oxidative and less glycolytic in its nature. PGC-1alpha almost certainly plays a significant

role in the pathophysiology of a variety of diseases, including diabetes, cardiomyopathy, and

obesity. In particular, its regulatory role in lipid metabolism makes it an enticing target for

pharmaceutical intervention in the treatment of obesity as well as Type 2 diabetes. This research

covers the significance of PGC-1 in skeletal muscle atrophy induced by immobility, as well as

summarises the current knowledge of the molecular basis of the peroxisome proliferator-

activated receptor- coactivator-1 (PGC-1)–mediated pathway. PGC-1 is the master transcription

regulator that is responsible for stimulating mitochondrial biogenesis. It does this by

upregulating nuclear respiratory factors (NRF-1, 2) and mitochondrial transcription factor A

(Tfam), which ultimately results in an increase in the amount of mitochondrial DNA replication

and gene transcription. PGC-1 stimulates the gene expression of superoxide dismutase-2

(SOD2), catalase, glutathione peroxidase 1 (GPx1), and uncoupling protein in order to manage

cellular oxidant–antioxidant equilibrium (UCP). Recent findings from muscle-specific PGC-1

overexpression highlight the significance of PGC-1 in atrophied skeletal muscle, reveal an

increase of the PGC-1 mitochondrial biogenic pathway, and result in decreased oxidative
damage. Therefore, it would suggest that PGC-1a has a preventive function against the

degradation of skeletal muscle that is connected to atrophy.

Mann Whitney test (nonparametric)

P value 0.0352

P value summary *

Significantly different (P < 0.05)? Yes

PGC-1a unquestionably plays a significant part in the process of preserving the metabolic

function of muscle and regulates a large number of genes that influence a wide variety of aspects

of muscle shape and physiological function.

Mann Whitney test (nonparametric)

P value 0.0038

P value summary **

Significantly different (P < 0.05)? Yes

p16 is a tumour suppressor protein that functions as an inhibitor of cyclin-dependent kinase and

plays a critical role in controlling the progression of the cell cycle. p16 is able to slow down the

cell cycle because it is able to inactivate cyclin-dependent kinases, which are the enzymes

responsible for phosphorylating Rb. The phosphorylation state of Rb is a secondary factor that

affects p16 gene expression. Infection with the human papilloma virus (HPV) may cause the

oncogenes E6 and E7 of the HPV to inactivate pRB, which then results in an overexpression of

p16. As a result, p16 overexpression is a surrogate biomarker of HPV infection (in particular
high-risk HPV types), which makes it helpful in assessing HPV-associated squamous and

glandular neoplasia of the lower gynecologic tract.The significance of the intensity and

distribution of p16 in terms of interpretation, as well as its nuclear vs cytoplasmic localization,

will be covered in the next section of this chapter. There are additional methods of p16

overexpression that are not reliant on HPV, hence it is possible to find p16 expression in tumours

that do not always include HPV infection, such as ovarian serous carcinoma. Sarcopenia was

characterised as the occurrence of both reduced muscle mass and poor muscular function.

Presarcopenia was characterised as decreased muscle mass with normal muscular function.

Control was defined as normal muscle mass as well as function. When compared to young adult

wild-type (YWT) mice, the maximum force produced by control muscles of older satellite cell

knockout SIRT1 mice was considerably lower (P 0.001) than that produced by YWT mice.

After recovery from CTX injury, the mean contraction force at 40 Hz stimulation was

considerably higher in older mice that overexpressed muscle SIRT1 than in age-matched SIRT1

knockout animals (P 0.05). This was the case in older mice that overexpressed muscle SIRT1.

SIRT1 muscle knockout animals (P 0.05) showed higher levels of p53 in CTX-damaged

tissues as compared to YWT CTX mice. This was a statistically significant difference. When

compared to wild-type or SIRT1 deletion mice, SIRT1 overexpression with co-expression of p53

was related with greater fatigue resistance and higher force potentiation during repeated

contractions (P 0.001). This was the case regardless of whether or not p53 was also expressed.

However, the proliferation of satellite cells was significantly greater in older mice with SIRT1

muscle knockout (P 0.05), but not in older mice with SIRT1 satellite cell knockout models in

vitro, although this effect was attenuated in vivo after 21 days of recovery. Muscle structure and

mitochondrial function were not different between the groups. Through calcium signalling
stimulation of MEF2C/MEFD and CREB transcription factors, exercise is able to trigger PGC-1a

transcription in skeletal muscle. Activation of PGC-1a transcription in skeletal muscle occurs as

a result of communication between the energy-sensing kinase AMPK as well as the stress-

inducible kinase p38 MAPK (mitogen-activated protein kinase). The age-related loss of skeletal

muscle that leads to sarcopenia is the medical term for this condition. [Citation needed] 1

Sarcopenia is associated with an increased risk for physical disability, fall-induced injuries,

hospitalization/institutionalization, and death,2 and it is made worse by obesity and metabolic

diseases.

Sarcopenia is also associated with an increased risk for mortality. 3 Sarcopenia may be

caused, in part, by mitochondrial malfunction, which is responsible for the regulation of muscle

metabolism. 4 It has been shown that mitochondrial size and granularity may change with age 5,

6, and that this also occurs in the mitochondria of people who have been diagnosed with type 2

diabetes mellitus. 7 Aging and metabolic illnesses both have a role in the loss of mitochondrial

function, however other evidence shows that age-associated changes in mitochondrial

morphology occur regardless of a person's lifetime. 9 It is interesting to note that it is generally

believed that highly oxidative type I muscle fibres are more resistant to the muscle wasting that

is associated with sarcopenia than type II muscle fibres, which have a lower volume of

mitochondria (3%) than type I fibres (6%). 11 Type II muscle fibres have a lower volume of

mitochondria (3%). 10 One possible explanation for this is that mitochondria in type II fibres are

more susceptible to oxidative stress than mitochondria in type I fibres. 12 Therefore, maintaining

mitochondrial activity is a viable method for minimising sarcopenia in both kinds of fibre.

[Citation needed]
 Sirtuin 1 (SIRT1) is a class III histone deacetylase that needs NADH in order to

deacetylate its substrates. Because of its dependence on NADH, SIRT1 is very sensitive to

changes in metabolism. Overexpression of the gene SIRT1 has been associated to extended

lifespans in a number of different creature models. This finding suggests that SIRT1 may be the

missing connection between calorie restriction and longevity. In addition, it has been shown that

SIRT1 may prevent type I fibre atrophy brought on by intermittent fasting by deacetylating

FoxO1 and FoxO3 and therefore preventing their ability to carry out their transcriptional duties.

In addition, activating SIRT1 in muscle cells reduces the decrease in slower fibre type myosin

heavy chain (MHC) gene expression as well as the wasting of myotubes in response to glucose.

It is important to note that SIRT1 has been shown to be a regulator of protein peroxisome

proliferator activated receptor gamma coactivator 1 (PGC1), which is a well-established

regulator of mitochondrial biogenesis and glycolytic-to-oxidative fibre type switching in human

skeletal muscle. Activation of PGC-1, also known as deacetylation, takes place as a result of

AMPK's activation of the deacetylase SIRT1. In point of fact, the deacetylation of PGC1 by

SIRT1 causes an increase in the expression of critical genes involved in glucose and lipid

metabolism. SIRT1 deacetylation is believed to be under the control of the acetyltransferase

GCN5. Despite the fact that mitochondrial biogenesis in response to exercise is not affected in

SIRT1 knock out situations.

A malfunction in satellite cells is an additional factor that may contribute to the loss of

muscle in sarcopenia.Satellite cells are a kind of mononucleated muscle stem cell that are

accountable for the bulk of the muscle regeneration that occurs after an injury. It has been

demonstrated that the expression of SIRT1 and satellite cell populations decreases with

aging.This raises the possibility that increasing the expression of SIRT1 in older muscle models
might act as a countermeasure to preserve muscle regenerative capacity and, as a result, improve

muscle function after muscle injury in ageing. In line with this theory, resistance training

combined with the ingestion of resveratrol, a substance that is known to activate SIRT1,

enhanced satellite cell proliferation and improved muscle fibre size and function in the muscles

of older individuals to a larger degree than resistance training alone. In addition, resveratrol

inhibits the death of cells and promotes the development of myotubes while inhibiting SIRT1

results in more cell death and less differentiation. In addition, it has been shown that SIRT1 is

responsible for keeping satellite cell pools in a quiescent state, and a lack of SIRT1 activity has

been demonstrated to result in the premature differentiation of muscle satellite cells. It has been

found that moderate endurance exercise, which increases SIRT1, may reverse an aging-induced

decline in satellite cell counts in rats. This finding lends credence to the aforementioned theory.

However, other investigations have found varied patterns of SIRT1 expression depending on age

and tissue type, which calls into question whether or not becoming older has universal effects on

SIRT1. Therefore, in the context of muscular sarcopenia, there is a need for more research into

the role that SIRT1 plays in the control of mitochondrial function and satellite cell activity in the

process of muscle healing. Following acute injury to skeletal muscle in older mice, the goal of

this work was to evaluate the role that SIRT1 plays in the process of mending muscle and

restoring skeletal muscle function.

Our working hypothesis was that overexpression of SIRT1 in muscle improves

mitochondrial function as well as satellite cell activation, which in turn improves muscle repair

and function after acute injury. On the other hand, loss of SIRT1 in muscle as well as satellite

cells of older mice reduces muscle repair as well as function after injury by suppressing satellite

cell activation as well as increasing the amount of time it takes for mitochondria to repair
damage. To our surprise, we discovered that the abundance of SIRT1 in skeletal muscle does not

have a significant impact on either the performance of muscles or the recovery of skeletal muscle

after injury. On the other hand, we discovered that the deletion of SIRT1 in satellite cells inhibits

the function and repair of muscles. However, the abundance of SIRT1 may function in

conjunction with p53 to lower the amount of muscular fatigue that occurs during muscle healing

after muscle damage.

Mann Whitney test (nonparametric)

P value 0.7413

P value summary ns
Significantly different (P < 0.05)? Yes

The most prevalent kind of tissue in the body is called skeletal muscle. The formation of

a skeletal muscle cell is a complicated process that is influenced by a variety of circumstances.

The process of myogenesis is controlled by a vast number of microRNAs (miRNAs), which have

been identified as essential regulators. It has been suggested that the muscle-specific miRNA

known as MiR-208b is involved in the process of determining the type of fibre. However, it has

not yet been determined if miR-208b has any influence on the proliferation of muscle cells. In

the research that we conducted, the gene cyclin-dependent kinase inhibitor 1A (CDKN1A),

which is involved in the control of the cell cycle, was first predicted to be a target of miR-208b

and then verified to have that status. We discovered that overexpression of miR-208b in cow

primary myoblasts in vivo and in vitro led to an increase in the expression of cyclin D1, cyclin

E1, and cyclin-dependent kinase 2 at the levels of messenger RNA and protein respectively. This

was the case in both experimental settings. Flow cytometry revealed that inducing cells to

forcefully express miR-208b led to an increase in the proportion of cells that were in the S phase

and a reduction in the proportion of cells that were in the G0/G1 phase. Based on these findings,

it was shown that miR-208b is involved in the process of regulating the cell cycle in cow primary

myoblast cells. Assays using 5-ethynyl-20-deoxyuridine and 3-(4,5-dimethylthiazol-2-yl)-2,5-

diphenyltetrazolium bromide demonstrated that overexpression of miR-208b stimulated the

proliferation of cow primary myoblasts. As a result, we have arrived at the conclusion that miR-

208b plays a role in the control of the cell cycle and proliferation of cow main skeletal muscle

cell via the posttranscriptional downregulation of CDKN1A.

Discussion
Primary sarcopenia is a disorder that is characterised by decreased skeletal muscle mass

and strength, decreased agility, increased fatigability, and increased risk of bone fractures. This

disease is typical in elderly persons who are otherwise healthy. There are still some gaps in our

understanding of the pathophysiology of primary sarcopenia. In this article, we discuss the

fundamental aspects of the cellular and molecular mechanisms that are responsible for the

maintenance of skeletal mass; the alterations of myofiber metabolism and deranged properties of

muscle satellite cells (the adult stem cells of skeletal muscles) that are at the root of the

pathophysiology of primary sarcopenia; the function of the Ca2+-sensor protein, S100B, both as

an intracellular factor and as an extracellular signal that regulates cell functions; and the

functional role Building on recent results that point to S100B as a molecular determinant of the

transition from myoblasts to brown adipocytes, we propose that S100B acts as a transducer of the

deleterious effects of accumulation of reactive oxygen species in myoblasts as well as,

potentially, myofibers, which are associated with the pathophysiology of sarcopenia. Alterations

in the content of satellite cells are an important factor in the regulation of skeletal muscle

development and atrophy. However, there is a paucity of data about the changes that occur in the

composition of satellite cells in humans from birth to old life. This research aims to determine

the percentage of muscle fibre type-specific satellite cells that are present in human skeletal

muscle tissue over an individual's whole lifetime. Muscle biopsies were taken from a total of 165

subjects, including children younger than 18 years old who were undergoing surgery (n = 13),

young adults aged 18 to 49 years old (n = 50), older adults aged 50 to 69 years old (n = 53), and

senior citizens aged 70 to 86 years old (n = 49). Biopsies were taken from different muscles in

the children. After 12 weeks of supervised resistance-type exercise training, further biopsies
were taken from a subset of 51 elderly adults with an average age of 71 years and a standard

deviation of 6 years.

The use of immunohistochemistry allowed for the evaluation of the particular

composition, size, and number of satellite cells found in skeletal muscle fibres. The size of

muscle fibres dramatically grew from birth to maturity, but there was no significant change in the

amount of satellite cells contained inside muscle fibres, and there was no distinction between

type I and type II muscle fibres. When compared to type I muscle fibres, the size of type II

muscle fibres was shown to significantly decrease with increasing age in adults (r = 0.56; P

0.001; see also:). This was followed by an age-related decrease in the content of type II muscle

fibre satellite cells (r = 0.57; P 0.001) in the muscle fibres. Training of the resistance kind for a

period of twelve weeks considerably enhanced the size of type II muscle fibres as well as the

satellite cell content. We come to the conclusion that the atrophy of type II muscle fibres that

occurs with age is accompanied by a distinct reduction in the amount of type II muscle fibre

satellite cells. Training with various forms of resistance is an excellent technique for increasing

satellite cell content and reversing type II muscle fibre atrophy. Hayflick and Moorhead (1961)

made the important finding that cellular senescence is a process that globally affects cell destiny

and may be regarded a characteristic of ageing (López-Otn et al., 2013). Cellular senescence is a

process that can be considered a hallmark of ageing. Hayflick proved that typical human diploid

fibroblast cell strains would stop dividing in vitro after a predetermined number (40–60) of

population doublings after being subjected to serial passaging. This number is referred to as the

Hayflick limit Senescence may be caused by a variety of developmental cues as well as many

forms of stress.
 Cells may react to stress by causing repair, cell death, or senescence depending on the

kind of cell, the level of the stress, and the cause of the stress. In response to a wide variety of

intrinsic and extrinsic stimuli, cells are able to go through the process of senescence. Some of

these stimuli include progressive telomere shortening, changes in telomeric structure, mitogenic

signals, oncogenic activation, radiation, oxidative and genotoxic stress, epigenetic changes,

chromatin disorganisation, perturbed proteostasis, mitochondrial dysfunction, inflammation,

and/or tissue damage signals ,These various kinds of stress signals can result in a number of

distinct forms of senescence, such as telomere-dependent replicative senescence, programmed

senescence, or non-telomeric stress-induced premature senescence. Other forms of senescence

that can be caused by stress signals include oncogene-induced senescence (OIS), senescence

caused by unresolved DNA damage, epigenetically induced senescence, and More than fifty

different tiny chemical compounds have been shown to be capable of inducing premature

senescence and senescence-like states, according to a comprehensive investigation that was

conducted by Petrova et al. (2016). Recent research has shown that treatment with certain

anticancer agents, chemotherapeutic drugs, or ionising radiation can cause tumour cells to

experience "therapy-induced senescence" (TIS) It is now believed that senescence is a highly

dynamic, multi-step process, during which the characteristics of senescent cells continually

change and diversify in a way that is reliant on the surrounding environment .It is linked with a

number of different cellular and molecular modifications as well as various phenotypic

abnormalities, one of which is a proliferative arrest that is persistent and typically irreversible, as

well as insensitive to mitogenic stimuli.

Senescent cells are normally resistant to apoptosis and may continue to function normally

despite changes in their metabolic activity They engage in a DNA damage response (DDR) that
is persistent and go through substantial alterations in gene expression as well as chromatin

remodelling and chromatin remodelling .Increased lysosomal activity macromolecular damage

and a temporal cascade in the development of the complex senescence-associated secretory

phenotype (SASP) are some of the distinguishing characteristics of senescent cells .In addition,

senescent cells are capable of developing morphological and structural changes, such as an

enlarged, flattened, multinucleated morphology with enlarged vacuoles an altered composition of

the plasma membrane, and a remarkable nuclear enlargement. Senescent cells can also undergo a

remarkable nuclear enlargement .These intricate alterations to the cell serve the purpose of

putting many components of senescence into action, such as the inhibition of growth and the

formation of the SASP secretome.At first, scientists believed that senescence was an artefact

caused by tissue culture. On the other hand, a number of investigations that have been conducted

afterwards have shown that senescence is important in a variety of physiological and

pathological processes .Normal development maintaining tissue homeostasis, tissue remodelling

and repair (Yun et al., 2015), wound healing secretion of insulin by pancreatic beta cells and

senescence limits tumour progression by ( ).It has been shown that the

accumulation of senescent cells in numerous organs occurs in an exponential fashion with

increasing chronological age (Muoz-Espan and Serrano, 2014; Hudgins et al., 2018). The early

work of Hayflick and Moorhead (1961) for the first time provided a hint toward a relationship

between senescence and ageing. However, subsequent discoveries have demonstrated the

presence of senescent cells in vivo and an increase in their number with age, providing support

for the hypothesis that senescence itself can drive ageing and is one of its key hallmarks

(Hayflick and Moorhead, 1961; Hayflick, 1965; López-Otn

 The accumulation of senescent cells, the depletion of stem/progenitor cell compartments,

and the secretion of SASP are all factors that contribute to the ageing of tissues and

organisms .Cellular senescence also has negative effects because it can impede tissue repair and

regeneration and contribute to the ageing of tissues and organisms. Senescent cells have been

identified in a variety of age-related disorders, including atherosclerosis, diabetes, lung disease,

and many others . In spite of the fact that senescence is closely linked to becoming older, cells

may enter senescence for reasons unrelated to the age of the organism, such as shortening of the

telomeres or other signals. Accordingly, the utilisation of transgenic mouse models has enabled

the detection of senescent cells in a variety of age-related pathologies and has made it possible

for the development of genetic or pharmacological strategies to demonstrate that the selective

elimination of senescent cells can prevent or delay age-related tissue dysfunction in order to

extend life span and improve health span. This is in accordance with the previous statement .It is

believed that cellular senescence is an example of evolutionary antagonistic pleiotropy because it

has both positive and negative effects on the health of the organism Cellular senescence is a

programme that When considered as a whole, senescence is a programme that is both

physiologically essential and pathologically significant; yet, its function is contingent upon the

environment and the particular circumstances. In this article, we will go through the several

processes that influence cellular senescence, with a particular emphasis placed on cell cycle

arrest and SASP.

We focus on the key mediators, characteristic hallmarks, and the various pathways that

are involved in manifesting cellular senescence as well as the cell cycle arrest and its key

regulators along with the role of the DREAM complex and its associated components. We also

detail the complexity of the mechanisms that are involved in SASP regulation. The relevance of
cellular senescence in a variety of circumstances, including its function in vivo, in cancer, and in

the process of ageing, is also covered in this article. At the end, we discuss the translational

relevance and suitability for identifying and characterising senescent cells in vivo to explore

potential future avenues for exploiting the benefits and preventing the detrimental aspects of

senescent cells such as suppressing the SASP or selectively eliminating senescent cells to

increase health span. This is done in order to explore potential future avenues for exploiting

potential future avenues for exploiting the benefits and preventing the detrimental aspects of

senescent cells.The molecular signatures of sarcopenia compared to those of healthy older people

revealed a low mitochondrial bioenergetic capacity as the dominant signal in the transition from

physiological to pathological muscle ageing across ethnic groups. Sarcopenia is a condition that

affects the ageing of muscles and is associated with a loss of muscle mass.

Oxidative phosphorylation and mitochondrial energy homeostasis were the most

perturbed biological processes associated with sarcopenia in all ethnicities. Bioenergetic

alterations spanned across all mitochondrial respiratory complexes, both at the level of

expression and activity. Sarcopenia is characterised by a loss of muscle mass and an increase in

the percentage of fat in the body. In human sarcopenia, we also found transcriptional markers of

altered mTOR signalling, translation, and protein synthesis, which is consistent with the

involvement of anabolic resistance in the gradual loss of muscle mass and strength that occurs

with aging33,34. On the other hand, neuromuscular dysfunction was not enriched in the

transcriptional signature of sarcopenia, and elevated inflammatory signalling was confined to

certain but not all cohorts of human sarcopenia patients. [Citation needed] These processes,

which were documented in preclinical models4,8,35 of muscle ageing, may impact sarcopenia

via nontranscriptional pathways or in patient subgroups; nonetheless, our results indicate that
these mechanisms are not fundamental characteristics of human sarcopenia. The molecular

footprints of sarcopenia in skeletal muscle were most strongly influenced by muscle mass and

strength, with more modest contributions from gait speed. This may be because other

mechanisms that influence this multifactoral measurement of mobility and quality of life diluted

the significance of gait speed's contributions. The capacity to maintain a high level of oxidative

phosphorylation has been shown to have a favourable association with high levels of muscle

mass, grip strength, and gait speed when evaluated independently and continuously. As a result

of these results, an altered mitochondrial bioenergetic capability is established as a powerful and

conspicuous factor of the transition to impairment in old skeletal muscle. This is achieved by a

reduced oxidative phosphorylation.

Reduced expression or activity in sarcopenic muscle of the transcriptional regulators

ERR and NRF1 and their coactivator PGC-1 is associated with mitochondrial alterations in

sarcopenia at the molecular level. This is because mitochondrial alterations in sarcopenia involve

the perturbation of a transcriptional module. The ability of these transcriptional regulators to

control the expression of mitochondrial genes in rodents and humans has been proven to a high

degree (30,31). Particularly, overexpression of PGC-1 or ERR is sufficient to induce the

expression of genes controlling mitochondrial function and to trigger functional benefits on

oxidative phosphorylation and ATP generation. This is the case even though neither gene is

directly involved in mitochondrial function. Therefore, the downregulation of PGC-1 and ERR

target gene expression networks in sarcopenic muscle implies reduced transcriptional activity of

ERR and possibly of other PGC-1-dependent transcription factors. This could possibly explain

the global mitochondrial dysfunction that is observed in sarcopenia. It is interesting to note that a

disruption in the NRF1 signalling pathway was only found via the transcriptional downregulation
of its direct target genes; nevertheless, the level of its expression was not altered by sarcopenia.

In contrast, sarcopenia was associated with a reduction in the expression as well as the

transcriptional effectiveness of PGC-1 and ERR on their respective target promoters. This

observation is consistent with a priming function of low-PGC-1/ERR signalling in reducing

oxidative phosphorylation and initiating pathological muscle decline. PGC-1 and ERR act

cooperatively through direct binding of PGC-1 to ERR on target promoters and through a feed-

forward loop where ERR or PGC-1 activate the expression of their own promoters31. Both of

these mechanisms reduce oxidative phosphorylation and initiate pathological A large cluster of

MRPs was downregulated in sarcopenia, which most likely contributed to the decreased protein

expression of mitochondrial respiratory chain subunits. Translational mechanisms overlapping

with this transcriptional regulation also occurred, as shown by the fact that sarcopenia caused

this cluster of MRPs to be downregulated. MRPs are also critical for maintaining the correct

balance of mitonuclear communication as a result of ageing and for regulating a protective

mitochondrial UPRmt, which is essential for the control of healthspan and longevity in

preclinical models32. In sarcopenic muscle, there was a decrease in the expression of UPRmt

genes, which include mitochondrial heat-shock proteins, proteases, and the downstream

transcriptional response that regulates mitohormesis from the nucleus. Because of this, the

inadequate activation of UPRmt that occurs during sarcopenia is unable to compensate for the

altered synthesis of respiratory chain components and the damage to mitochondrial proteins that

is caused by oxidative stress10,17.

Additionally, we found molecular signals in sarcopenic muscle that indicated altered

mitochondrial dynamics via the process of fusion and fission. In preclinical models of muscle

disease and aging11, a relationship has been shown between the regulation of mitochondrial
dynamics and the control of metabolic processes and plasticity in skeletal muscle. It is interesting

to note that the genetic loss of function of Mfn2 and Opa1 in mice is sufficient to generate

sarcopenia43,44,45. This finding suggests that the down regulation we found in sarcopenia might

be causative in the loss of muscular mass and strength.The NAD+ loss that occurs with ageing is

well recognised in preclinical models, and it has just recently been discovered to occur in

humans, where NAD+ levels in both the skin and the brain fall over the course of a lifespan46.

The reduction of skeletal muscle NAD+ levels in people with sarcopenia links for the first time

NAD+ levels to an age-related pathology in humans and provides the first proof-of-principle of

altered NAD+ biosynthesis in human skeletal muscle. Despite the fact that our NAD+ results

require further validation because they were analysed in a subset of individuals with sufficient

amounts of remaining muscle biopsy from SSS, this finding is significant because it establishes a

link between NAD+ However, mitochondria only represent 5–10 percent of myofiber volume47,

and NAD+ is also abundant in larger cellular compartments48, which most likely also accounts

for the sarcopenic NAD+ phenotype. Therefore, it is possible that low amounts of mitochondria

in human sarcopenia could potentially contribute to reduced NAD+ levels given the high

mitochondrial NAD+ concentration. Alterations in metabolic fluxes are yet another option that

might lead to the depletion of NAD+. These alterations could be caused by mitochondrial

activity that has been disrupted. However, low levels of NAD+ are a causative mechanism for

mitochondrial disturbances that are associated with age-related diseases in model

organisms49,50,51. Reduced levels of NAD+ in the skeletal muscle of aged or Nampt deficient

mice alter mitochondrial bioenergetics and result in impaired muscle mass, strength, and

endurance49,50,52,53.
 These findings suggest that low levels of NAD+ in sarcopenic people may directly

contribute to impaired mitochondrial activity and the progression of sarcopenia in humans.

Importantly, new therapeutic strategies have emerged in order to restore NAD+ levels in muscle

through the administration of dietary NAD+ precursors such as NR or NMN46,53,54. The

conversion of these precursors to NAD+ bypasses the rate limited enzyme NAMPT, which is

downregulated in sarcopenia. This is an important development. In conjunction with previous

research that has shown these interventions to be risk-free and to increase levels of NAD+ in

early human clinical testing46,55,56, the results of our study provide the mechanistic foundation

necessary to test the clinical efficacy of NAD+ precursors on muscle strength and physical

function in older people who suffer from sarcopenia. In a broader sense, the findings of our study

underline the need of taking into consideration dietary and pharmacological mitochondrial

therapies for the treatment of sarcopenia. This can be accomplished by stabilising the

mitochondrial machinery by targeting cardiolipin57, promoting the elimination of damaged

mitochondria by mitophagy with the natural molecule Urolithin A18,58, or targeting energy

sensors such as AMPK, PPARs, and sirtuins that converge on PGC-1 signaling30. Alternatively,

this can be accomplished by targeting PGC-1 signaling30. The well-documented advantages of

regular physical exercise for the mitochondrial function of older skeletal muscle Exercise

regimens designed to treat sarcopenia should also promote mitochondrial adaptations that boost

bioenergetic coupling, according to research published in 2, 47, and 59. The findings of the

MEMOSA project, when taken as a whole, offer a biological resource covering the whole of the

genome, including processes and indicators of pathological muscle ageing across ethnicities. Our

research establishes that the loss of mitochondrial oxidative capacity is a major mechanism of

sarcopenia, which can be evaluated non-invasively by using 31P imaging as a biomarker60, and
it also provides a strong rationale for intervention trials targeting muscle mitochondrial

bioenergetics in order to manage sarcopenia in older people.

Conclusion

The process of ageing is a multifactorial phenomenon that is characterised by multiple

overlapping physiological and molecular changes. Previous studies that looked at skeletal muscle

in elderly people and young adults made a comparison of the two groups in order to determine

the mechanisms that drive muscle ageing. However, these studies did not differentiate between

the mechanisms that specifically lead to pathological decline as well as physical

disability38,39,40,41. A few candidate genes and pathways connected to pathological muscle

ageing have been deconvoluted by the use of candidate-based approaches42 in light of the recent

designation of sarcopenia as a distinct pathological condition . We report the first integrated

molecular profile of human sarcopenia across ethnicities in the MEMOSA multicenter study.

This was accomplished by conducting a comparison of the muscle transcriptome in older people

with physical disability to healthy controls of the same age group using genome-wide

transcriptional profiling and functional validation. Our research not only establishes significant

advancements in the mechanistic understanding of sarcopenia pathophysiology by characterising

the mechanisms that lead to physical disability, but it also offers a one-of-a-kind resource for the

identification of novel molecular targets and biomarkers to prevent sarcopenia and promote

skeletal muscle health in people who are older.

Even though the pathophysiology of primary sarcopenia has not been completely

elucidated, there is widespread agreement that a ROS imbalance brought on by cell senescence,

defective quality control of mitochondria, reduced physical activity, and/or an excessive calorie
intake is one of the primary causes. In turn, a ROS imbalance may lead to a reduction in the

proliferation and differentiation capabilities of muscle stem cells (SCs), which are essential for

the upkeep of skeletal muscle mass, as well as a depletion of the SC reserve pool. In myofibers,

an imbalance of ROS may also arise, which can stimulate metabolic processes that can lead to

the breakdown of myofibrillary protein, commonly known as muscular atrophy. Several extrinsic

and intrinsic variables have been demonstrated to work together to generate alterations in SCs,

which eventually result in altered SC/myoblast dynamics as well as an impaired capacity to

proliferate and repair injured myofibers. Although SCs were required for reducing sarcopenia-

associated muscle fibrosis and for muscle regeneration in aged mice following acute injury,

recent studies using mice in which SCs had been genetically ablated cast doubt on the possibility

that alterations in SC properties might play a fundamental role in the pathogenesis of primary

sarcopenia. This is despite the fact that SCs were required for reducing sarcopenia-associated

muscle fibrosis. Therefore, satellite cells may not play a part in the pathophysiology of

sarcopenia in elderly sedentary individuals, in whom muscle atrophy may be caused solely by

disturbed myofiber metabolism.

On the other hand, satellite cells may be important players in the pathophysiology of

sarcopenia in elderly non-sedentary individuals to mitigate the progression of sarcopenia because

of their ability to regenerate exercise-damaged muscles. Additional research is required on this

matter. S100B is emerging as an extrinsic factor acting on at least macrophages and myoblasts to

regulate the timing of muscle regeneration following acute (reversible) muscle injury and during

the acute phase of muscular dystrophy. It is also emerging as an intrinsic factor accumulating in

SCs/myoblasts and, likely, myofibers in chronic oxidative conditions under the action of a

ROS/NF-B axis, dampening myogenic differentiation and promoting myo We propose that
S100B acts as a transducer of the deleterious effects of accumulation of ROS in myoblasts and

myofibers, which is congruent with the pathophysiology of sarcopenia. While the potential role

of S100B in the quality control of proteins and organelles still needs to be investigated, we

propose that S100B acts in this capacity. It is generally agreed that skeletal muscle satellite cells

play an important part in the process of maintaining, repairing, and remodelling muscle fibres.

Traditionally, in vitro cell models and in vivo animal models have been used to inform our

understanding of the function that satellite cells play in the adaptation process of muscle fibres.

Since the beginning of this decade, there has been a concerted attempt to apply these findings to

people while maintaining their physiological state. In human subjects, in vivo research suggests

that satellite cells play a significant part in the process of repairing and modifying skeletal

muscle fibres in response to physical activity. There is an accumulation of information pointing

to the conclusion that ageing has a significant influence on the control of satellite cells in human

skeletal muscle. However, the specific function that satellite cells play in the ageing process-

related loss of muscle fibres has not been conclusively established as of yet. This review tries to

incorporate current findings from in vivo human investigations on satellite cell activity in muscle

fibre repair/remodeling into the larger framework of satellite cell biology, the literature of which

is mostly focused on animal and cell models. These studies were conducted on human subjects.